WO2013067608A1 - Immunomodulating compound for the treatment of cancerous tumours that are located in the internal and external epithelial tissue - Google Patents

Abstract

The present invention provides a novel adjuvant treatment for cancerous tumours that are located in the epithelial tissue lining external and internal surfaces, comprising the topical administration of a compound that modifies the biological response, said compound being used alone or associated or combined with other drug treatments and non-drug treatments.

Description

 "IMMUNOMODULATOR COMPOUND FOR TREATMENT OF CANCER TUMORS LOCATED IN THE INTERNAL EPITELIAL FABRIC AND

EXTERNAL "This patent application is for a biological response modifying compound used alone or in combination or in combination with other medicated and non-medicated treatments comprising topical application providing a novel adjunctive treatment for cancerous tumors in the epithelial tissue of outer and inner coating

Epithelial tissue and cancer

 Epithelial tissue is a special type of cellular structure that lines the entire outer surface of the body or epidermis and all internal body cavities, such as the pleural, pericardial, and peritoneal cavities. It also forms the lining of the heart, blood and lymphatic vessels, digestive tract and genitourinary tract.

It consists almost exclusively of juxtaposed cells, with very little or no intercellular substance between them. The cells are adhered to each other by intercellular junctions or by cell membrane proteins.

 The lining epithelial tissue does not have its own vascular system and its cells are nourished by diffusion from adjacent connective tissue.

The epithelial tissue performs several important functions, including the following: Protection and lining (eg skin), secretion (eg stomach), mixed secretion and absorption functions (eg intestine), waterproofing (eg bladder) urinary tract).

Finally it should be noted that just as in any and all cellular tissues, malignant tumors may originate in the epithelial tissue, and it is noteworthy that a large proportion of human and animal malignant tumors originate or localize in this particular type of fabric.

This is not surprising given the fact that epithelial tissue, due to its characteristics and functions, is endowed with cells that must be constantly renewed and that, in addition, they are almost continuously exposed to aggressive external agents such as solar radiation and potentially carcinogenic chemicals. . Epithelial tissue and treatment modalities

 It should also be noted that since the epithelial tissue does not have its own blood supply system, this makes it difficult or unfeasible to use drugs or medicines that depend on transport routes such as the vascular or lymphatic system to reach the tissues of this epithelial. specific anatomical region.

 This is relevant for the treatment of malignant lesions located in the superficial layer of the lining epithelium as the use of therapies using systemic agents is ineffective or virtually useless for treating malignant or premalignant lesions located in the surface lining. external or internal.

 Therefore, in the current state of the art, medicine seeks to use special treatment techniques and procedures, such as surgical procedures, radiotherapy and even drugs that are also capable of localized or topical action to act more effectively on the lining epithelium.

The primary objective of localized or topical treatment of tumors in this specific region is to eradicate tumors from the lining epithelial tissue before they spread to other adjacent tissues and then diffuse into the body.

 For purposes of the present invention and to facilitate understanding of the state of the art it is relevant to mention that the lining epithelial tissue can be accessed for therapeutic purposes, i.e. performing localized or topical treatment both outside and inside the organism.

 This is the case, for example, for skin tumors which are treated locally by surgical removal, radiotherapy, phototherapy and chemotherapy, which may be used alone or in combination.

 Likewise, tumors in the internal epithelial tract (eg stomach, intestine, urinary bladder) can be topically treated and treated by surgical procedures, radiation of various types and even drugs capable of depositing or delivering drugs in the region of interest. .

In the particular case of medications, some special techniques and equipment may be used for their stay in the region of interest long enough to exert topical action on the affected tissue. For example, the treatment of urinary bladder surface-lining epithelial tumors that are treated by irrigation or contact with chemotherapeutic agents, which are introduced into the urinary bladder through devices called catheters or probes, can be cited. bladders.

 Finally it is well known in the current state of the art that all types of treatments available against tumors affecting the epithelial lining tissue, ie surgical treatments, radiation treatments and finally drugs, can often be used in the practice of combined or associated form to maximize the therapeutic response.

 SAFETY REQUIREMENTS FOR THE DEVELOPMENT OF THERAPY FOR USE IN THE EPITELIAL SYSTEM

Drugs or procedures that may be used to treat malignant lesions located in the external or internal epithelial tissue should be able to act topically and ideally should have little or no ability to penetrate beyond the epithelium because of the risk of reaching blood vessels or other systems. transport and spread throughout the body may cause toxicity problems to other organs.

 As a general rule, it can be stated that any procedure or medicament developed for localized treatment of lesions or malignant tumors situated in the inner epithelium may be used to treat lesions and tumors situated in the outer lining epithelium.

 Reciprocal may not always be applied, ie some developed and suitable drugs and therapies for use in the outer lining epithelium are not indicated for use in the treatment of tumors within the inner lining epithelium due to toxicity problems.

 This is because the inner lining epithelium, in addition to its greater sensitivity to aggressive agents, has a higher degree of permeability than the inner lining epithelium.

Differences in permeability degrees between the inner and outer lining epithelium are directly related to the function performed by the organ of which they are part. This occurs, for example, in the case of the intestinal lining epithelium, which also has the ability to carry substances into the body and therefore It can absorb substances more easily than the skin, which performs functions related to protection against penetration of external agents inside the body and also elimination of substances outside the body, as occurs in the case of sweat.

In practical terms this prevents products having systemic toxicity that could be useful for therapeutic use on skin that has low relative absorption capacity cannot also be used for treatments in the intestinal region because of the high absorption capacity of the lining epithelium. of this other anatomical region.

As a practical example of a procedure commonly used for both types of epithelial surface, the treatment of cancerous lesions located on the stomach epithelium is cited by the use of high energy light pulses (laser), a procedure that is also widely used. to eradicate malignant skin lesions.

Treatments using caustic chemicals such as podophyllin used for wart removal and malignant or premalignant lesions on the epidermis cannot be used to treat lesions on the internal epithelium, such as the intestinal tract, because of their potential. to indiscriminately damage healthy tissue at best or at worst, be absorbed and cause severe or fatal intoxication. For example, podophyllin is a compound obtained from a Podophyllum emodi plant, used to remove superficial skin lesions, including malignant and premalignant lesions.

 Podophyllin has antimitotic properties, and thus inhibits cell growth, being effective in destroying malignant and premalignant lesions located in the outer lining epithelium. However its use in the inner lining epithelium is inadmissible because of its toxic properties and absorbability.

As another example, mention is made of the drug called imiquimod (IUPAC: 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine, Ci ₄ Hi ₆ N ₄ ), which is an immunomodulator. or local immune response modifier that exhibits high toxicity to various cell structures.

This compound is only licensed and permitted for localized treatment of premalignant lesions caused by HPV virus, such as so-called acuminate condyloma or cutaneous papilloma, and for the treatment of basal cell carcinoma located on the outer lining epithelium (skin). However, imiquimod cannot be used to treat malignant lesions in the lining epithelium, such as malignant lesions in the intestine, because of the possibility of absorption through the intestinal mucosa.

Finally, it should be noted that the primary purpose of treating malignant or premalignant lesions located on the inner and outer lining epithelium is the eradication of these lesions, before cellular alteration propagates to deeper layers than unlike superficial layers. They are highly irrigated and may allow cancer to spread and settle in other organs or systems.

When the lesion is already extending beyond the most superficial layer of the lining epithelium and reaching the basal layer or beyond, treatment with predominantly topical-acting drugs may not be effective as many compounds are only effective or may be used locally for problems of toxicity or permeability.

Therefore, the treatment of malignant lesions that may be infiltrating beyond the surface layer of the lining epithelium at the time of detection is problematic in practice because of the above reasons, requiring the use of other treatment modalities or the use of chemotherapeutic drugs with systemic effect, which are quite toxic for the most part.

For example, local immunotherapy with BCG vaccine used for localized treatment of lesions located in the urinary bladder lining epithelium is ineffective in treating infiltrating malignant lesions, ie lesions that are already extending beyond the superficial layer and invading the basal layer. or bladder muscle as detailed in this report.

In addition, BCG vaccine cannot be used for the treatment of infiltrating lesions, as this would require its introduction into considerable amounts into the body using systemic routes of administration to achieve the site of interest or effect, which is impracticable in practice because of its high systemic toxicity.

Thus, localized or topical immunotherapy with many of the existing therapeutic agents cited in the case of the example of urinary bladder cancer that is infiltrating the superficial layer to the muscular layer, for example, is ineffective, forcing the adoption of surgery. radical removal of the organ, a procedure that is cystectomy, whether or not accompanied by radiotherapy and systemic chemotherapy.

 Cystectomy, or partial or total removal of the urinary bladder, in the prior art is the procedure indicated in the prior art for tumors classified as invasive, and even superficial tumors that do not respond to standard therapy, which consists of local tumor resection surgery. immunotherapy or localized chemotherapy, as detailed in this report.

This surgical procedure (cystectomy) if on the one hand can. Avoiding the deepening or spread of cancer, on the other hand, causes loss of high quality of life for most patients.

 THE NEED FOR IMPROVEMENTS IN THE TECHNICAL STATE

From these examples provided, it can clearly be seen that in the state of the art due to considerable treatment deficiencies, there is a need for new treatment options for cancer originating or localized to the inner and outer lining epithelial tissue that can replace or complement the existing treatments, maximizing their efficiency.

 It would be highly desirable that these new treatments could be used without the occurrence of undesirable side effects, which are frequent in the existing state-of-the-art treatments or that could contribute to reducing their toxicity to end users.

 Creative or inventive activity should therefore be directed towards new therapeutic modalities, including new methods of treatment and compounds alone or in association with one another and which in comparison are in practice superior to existing treatments in terms of efficacy and safety.

If these therapeutic modalities, due to their characteristics or properties, proved to be capable of being used in the localized treatment of malignant lesions located both in the internal epithelium and additionally, without presenting toxicity or contributing to reduce the toxicity of existing treatments, this would undoubtedly represent a considerable improvement. state of the art.

If additionally these new treatments were also capable of being used or having a topical and systemic effect this would also represent another advance in the state of the art as they could be used at the same time to treat superficial and infiltrating lesions. The invention precisely meets the aforementioned needs by providing an immunomodulatory compound that innovatively allows localized treatment of malignant lesions located on both the inner lining epithelium and the outer lining epithelium, and ultimately without presenting relevant or impeding toxicity for practical use, unlike most compounds available in the prior art. And to make clear the usefulness, inventive activity and comparative advantages of the invention in this report at various times are practical examples of the use of the invention in malignant lesions situated on the inner and outer lining epithelium using experimental animals.

The results are presented solely for the purpose of illustrating the novelty, utility and advantages of the invention, but at no time is it intended to limit the scope or scope of the invention.

 The results of the experiments can be extrapolated so that the utility of the invention can be viewed broadly, that is, its utility for the treatment of all forms and types of malignant or premalignant lesions located in the epithelium. internal or external lining of various anatomical sites or regions.

 In this sense, the experiments described in the report will clearly show the usefulness of the invention for the treatment of lesions in the inner lining epithelium of organs having internal space or lumen, such as superficial malignant tumors of the urinary bladder wall. and also for lesions on the outer lining epithelium, such as lesions on the skin.

 Therefore, in this report, a number of experiments will initially be provided relating to the practical use of the invention in the treatment of cancer-induced experimental malignant lesions located within the internalized lining epithelium, i.e. the urinary bladder lining epithelium.

 Following these examples of practical use below, practical examples of the use of the invention will be provided in the treatment of premalignant viral-caused lesions situated in the outer (skin) and inner (uterus) lining epithelium.

Prior to the description of the experiments, an introductory summary will also be presented covering aspects considered relevant to the diseases and treatments existing in the state of the art. CANCER IN THE INTERNAL COATING EPITELIUM - BLADDER CANCER - STATE OF THE TECHNIQUE

 Among the malignant tumors that affect or originate in the lining epithelium, urinary bladder cancer stands out.

After prostate cancer, bladder cancer is the most common urinary tract tumor, and one of the most common cancers, with a 4: 1 percentage among men and women (American Cancer Society. Cancer Facts and Figures 2009. Atlanta, GA : American Cancer Society, 2009. http://www.cancer.org Accessed June 4, 2010.).

 Worldwide, over 300,000 new cases are diagnosed each year, [Ferlay J, Parkin DM, Pisani P (2001) GLOBOCAN 2000: cancer incidence, mortality and prevalence worldwide. IARC Cancer-Base No. 5. IARC Press, Lyon].

In economic terms, bladder cancer patients have the highest annual costs of treating all cancers in the United States according to health reports for this specific disease (Simons MP, O'Donnell MA, Griffith TS Role of neutrophils in BCG immunotherapy for cancer bladder Urol Oncol 2008; 26: 341-5, PubMed: 18593617)

TUMOR STANDARDIZATION CLASSIFICATION - TECHNICAL STATUS - The TNM SYSTEM

The so-called TNM System is the standard system for classifying malignant tumors in the current state of the art.

This system is organized and periodically reviewed by the International Union Against Cancer (TNM Classification of Malignant Tumors) caused by viral action and applies to all types of tumors, including bladder cancer. TNM System General Rules

 The TNM System aims to establish criteria to describe the anatomical extent of malignant disease and is based on the evaluation of three components:

T: The extent of the primary tumor

 N: Absence or presence and extent of regional lymph node metastasis

M: The absence or presence of distant metastasis The addition of numbers to these three components indicates the extent of malignant disease. In exemplary terms: TO, T1, T2, T3, T4, NO, NI, N2, N3, MO, M1.

 TUMOR CLASSIFICATION IN THE URINARY BLADDER

 According to the International Union Against Cancer classification by the TNM System, tumors in the urinary bladder can be classified as follows (Table 1).

: TABLE 1: Classification of urinary bladder carcinomas by the TMN system i _Tv í Primary tumor cannot be evaluated f No evidence of primary tumor

Noninvasive papillary carcinoma

; Tis I Carcinoma in situ: "flat tumor"

 .J. J j Tumor invading subepithelial connective tissue

 ¾

j I Tumor invading muscle

 1 T2 I T2a - Tumor invading the superficial musculature (inner half)

i | T2b - Tumor invading deep musculature (outer half)

 j Tumor invading perivesical tissue

 Í3 í 3a - microscopically

 j T3b - macroscopically (extra bladder mass)

 [Tumor that invades any of the following structures: prostate, uterus, vagina,

(pelvic wall or abdominal wall.

^< T4

 j T4a - Tumor that invades prostate, uterus or vagina.

 I T4b - Tumor invading pelvic wall or abdominal wall

About 75% of cases of tumors in the urinary bladder lining epithelium found at the time of diagnosis are classified as non-muscle invasive bladder cancers, ie classified by the TNM System as Ta, Tis, Tl. (Table 1).

These tumors classified as Ta, Tl, Tis, are confined to the most superficial urinary bladder mucosa or lamina propria.

The remaining 25% of the types, at the time of diagnosis, are classified as invasive tumors of the musculature, ie, located in groups T2, T3, T4 of the System. TNM (Table 1). For reference: (Heney NM, Ahmed S, Flanagan MJ, et al. Superficial cancer bladder: progression and recurrence. J Urol. 1983; 130 (6): 1083-1086).

Treatment strategies For the purpose of developing therapeutic strategies, tumors usually are divided into: superficial and invasive, and superficial tumors include those classified in stages Tis, Ta and Tl by the TNM System (Table 1). By this system, the penetration of the tumor tissue of the muscular layer already identifies invasive bladder tumors, ie T2, T3 and T4 (Table 1). Treatment

The initial approach for all bladder tumors is a surgical procedure called transurethral tumor resection, also called the abbreviation TUR.

 The so-called transurethral tumor resection (TUR) is the standard procedure for diagnosis, staging and also for the initial treatment of tumors in the urinary bladder lining epithelium.

 Briefly, transurethral tumor resection or TUR comprises surgical removal of tumors or lesions suspected of urinary bladder malignancy. Such tumors or lesions are removed (resected) with the aid of special handles, laser scalpels and / or electrocautery.

 Subsequently, and at the end of the procedure, tissue fragments are removed from the region by aspiration for anatomopathological examination and histological evaluation of the lesions found for tumor classification purposes, usually by the so-called TNM system to establish the need and / or type of subsequent treatment the patient should undergo.

The surgical technique called transurethral tumor resection (TUR) is well known in the state of the art and can be known in great detail, for example in the UAE guidelines on the treatment of noninvasive bladder urothelial carcinoma of the muscle layer. For example: Eur Urol 2008 Aug; 54 (2): 303-14. As already mentioned, after TUR, the removed tissue fragments are examined by various techniques, such as histological tissue analysis, to obtain tumor classification using the system. TNM, in order to establish the need and / or type of subsequent treatment that the patient should undergo.

 As will be explained in more detail in this report, for best risk epithelial tumors classified by the TNM system (Ta, Tl, Tis) the best available state of the art procedure is to perform local surgery (TUR) for removal and staging. tumors, followed by intravesical adjuvant therapy with the use of chemotherapeutic or immunotherapeutic compounds.

 As already mentioned in this report, in the state of the art, the best treatment for tumors originating from or affecting the inner or outer superficial lining tissue utilizes a combination of treatments, involving the removal of localized lesions by surgical procedures, followed by adjunctive treatment using medicinal or compounds capable of topical action.

 Therefore, in the case of bladder cancer, patients are also treated by a surgical procedure (TUR) for the removal and staging of lesions, followed by adjuvant intravesical treatment with chemotherapeutic and / or immunotherapeutic agents.

The main objectives of this post-surgical treatment in the case of tumors affecting the inner and outer lining epithelium and in the particular case of bladder cancer are the elimination of tumors that went unnoticed during the surgical stage and to prevent tumor recurrence.

 For invasive urinary bladder tumors (T2, T3, T4) and also superficial tumors (Ta, Ti, Tl) that do not eventually respond satisfactorily to standard therapy, the main alternative or indication for prior art treatment It is a surgical procedure called cystectomy, which consists in the total or partial removal of the urinary bladder.

State of the art treatments available

Although any malignant tumor, including those located in the epithelial region, has the potential to spread, in the specific case of patients with tumors located in the superficial bladder epithelial tissue, those with a disease classified as Ta, Tl, Tis (Table 1). present the highest risk of recurrence and progression if treated only by transurethral resection, ie, only by localized surgical removal of the lesions.

 Therefore, after surgical removal of the lesions (TUR), the best available treatment in the state of the art to prevent tumor progression or recurrence is the localized treatment of the bladder epithelium using chemotherapeutic and immunotherapeutic compounds.

 In the specific case of bladder tumor, localized (topical) treatment of the bladder epithelium using chemotherapeutic or immunotherapeutic drugs is called intravesical therapy or intravesical adjuvant therapy.

The so-called intravesical therapy is a topical treatment modality that in the specific case of the epithelium or epithelial surface of the bladder, basically consists in the deposition or availability of agents with anticancer properties inside the bladder, by appropriate means, where they should remain for a certain period. of time in contact with the affected epithelium.

The main objectives of adjunctive intravesical treatment are: To minimize the possibility of tumor persistence and recurrence, to inhibit the formation of new tumors and finally to avoid or slow the progression of superficial lesions in the epithelium to other tissues or organs.

 For purposes of illustration only, some examples of therapeutic agents used for the treatment of malignant urinary bladder epithelium in the prior art are given in Table 2.

According to the mode of action, these agents can be broadly classified into two groups or classes: Chemotherapy drugs and immunotherapy drugs. Chemotherapy drugs include all compounds capable of direct destructive action against tumor cells, while those classified as immunotherapeutic drugs include compounds that act indirectly because they are able to act on the patient's immune system, so that, in turn, after stimulated or unblocked by such compounds, will act against the tumor process by slowing or eliminating it. CHEMOTHERAPIC AND IMMUNOTHERAPIC DRUGS MOST USED FOR INTRAVESICAL APPLICATION IN BLADDER CANCER

CHEMOTHERAPIES ALSO POSSIBLE ACTION MECHANISMS

 Mitomycin C j Antibiotic, inhibition of DNA synthesis. - I

Thiotepa j alkylating agent,

¹ Doxorubicin [Inhibition of topoisomerase, inhibition of DNA synthesis.

 Gemcitabine [Inhibition of DNA and RNA synthesis

Valrubicin Inhibition of topoisomerase, inhibition of DNA synthesis.

 1 IMMUNOTHERAPICS | PPOOSSSSÍVVEEIISS MMEECCAANNIISSMMOOSS DDEE ACCEPTANCE

 ! Bacillus Calmette-Guérin

 Immune System Stimulation

j (BCG)

i _rf i ICM \ Immune system stimulation, lymphocyte activation,

interreron (I IN) _Antian j g j g _{EN i0} antiproliferative _COJ.

 ! Interleukin-2 (IL-2) j Immune System Stimulation

Chemotherapy and immunotherapy in bladder cancer - Main therapeutic agents As mentioned above, the treatment of malignant lesions in the lining epithelium is performed in combination, starting with the surgical removal of the lesions, and after the treatment of the anatomical region. affected by the use of chemotherapeutic and / or immunotherapeutic agents to eliminate residual lesions and to prevent tumor recurrence.

 In the present state of the art, in the case of post-surgical treatment of superficial urinary epithelial tumors, intravesical immunotherapy using agents capable of stimulating the immune system is considered a more effective therapeutic procedure when compared with the use of chemotherapeutic compounds. in terms of preventing tumor recurrence or recurrence. : For reference: Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, Tl, and Tis): 2007 update. J Urol. 2007; 178 (6): 2314-2330. Among the agents capable of exerting topical action in urinary bladder epithelial cancer, the most effective immunotherapeutic agent used in the state of the art is the BCG vaccine that was originally developed for prophylactic treatment of tuberculosis.

The use of BCG vaccine in the post-surgical treatment of tumor lesions in the urinary bladder inner lining epithelium began in the 1970s with the pioneering work of Morales and colleagues who developed a new and innovative practical use for a known and novel product. previously used only for tuberculosis prophylaxis. Since then it has established itself as the main postoperative treatment used in the state of the art for adjunctive treatment of epithelial cancer, especially urinary bladder epithelium cancer. For example, Alexandroff AB, Jackson AM, O'Donnell MA, James K. BCG immunotherapy of bladder cancer: 20 years on. The Lancet, Volume 353, Issue 9165, Pages 1689 - 1694, 15 May 1999.

 Injury risk classification and intravesical adjuvant therapy

Although the treatment of any epithelial lesion in the bladder region considered cancerous or with the potential to develop into cancer begins with the surgical removal of the lesion (TUR) and subsequent treatment, it may vary according to the degree or classification of the cancerous lesion.

For tumors classified as high risk of recurrence but with low risk of progression, the most commonly used treatment criteria indicate the need for intravesical adjuvant therapy after surgical resection of the lesions (TUR) using intravesical agents. . To this end, the American Urological Association (AUA) recommendations include adjuvant therapy using chemotherapeutic agents such as mitomycin C or immunotherapeutic agents such as BCG vaccine. (reference).

For patients with tumors classified as having tumoral lesions considered at high risk for recurrence and additionally at high risk for progression (Ta, Tl, Tis), the predominant recommendation in the state of the art after surgical resection of the lesions includes performing a early phase of treatment using only BCG vaccine, called induction phase or therapy followed by maintenance therapy using the same drug (BCG vaccine).

For reference, Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, Tl, and Tis): 2007 update. J Urol. 2007; 178 (6): 2314-2330.

In the prior art, the use of BCG vaccine intravesical therapy according to the results obtained in various clinical trials is clearly superior to the use of chemotherapeutic agents such as Mitomycin C. For example, results published by the American Urological Association (AUA) show a 5-year recurrence rate for 34% of patients treated with BCG induction therapy, followed by BCG maintenance therapy compared with at a 64% recurrence rate for patients treated with chemotherapy (Mitomycin C).

For these results, it is cited in the prior art: Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, Tl, and Tis): 2007 update. J Urol. 2007; 178 (6): 2314-2330.

Intravesical maintenance immunotherapy Maintenance therapy is defined in the state of the art as periodic exposure of epithelial tissue (urothelium) for considerable periods of time to an intravesical agent such as Mitomycin C or BCG.

Adoption of maintenance therapy has in practice proved to be an important strategy for decreasing tumor recurrence rate as well as disease progression to earlier and more aggressive stages.

The use of maintenance therapy with BCG vaccine after transurethral lesion resection (TUR) is considered in the state of the art as the most effective treatment for decreasing tumor recurrence rate compared to other intravesical agents. The most relevant reference in the art of the efficacy of maintenance therapy using BCG vaccine is the clinical study called SWOG 8507 conducted by the Southwest Oncology Group or SWOG.

In this study, that is, SWOG 8507 patients with high-risk cancerous epithelial lesions received maintenance therapy with BCG vaccine after surgery (transurethral resection or TUR) every 6 months compared to patients treated with who did not receive BCG therapy.

Maintenance treatment lasted for 3 years. All patients were followed for 5 years after the end of their treatments to assess disease recurrence. Only 16% of patients in the SWOG 8507 study completed the entire intended use period due to problems related to BCG vaccine toxicity. However of the treated patients, the non-recurrence rate after 5 years was 60% compared to the 41% non-recurrence rate in the same time period for patients who did not undergo maintenance therapy with BCG vaccine.

For references and results of study SWOG 8507, it is cited: Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance Bacillus Calmette-Guérin immunotherapy for recurrent TA, TL and transitional in situ carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000; 163 (4): 1124-1129.

Following this study, the use of BCG vaccine after transurethral resection (TUR) of the tumoral lesions was definitively established in the state of the art as the best treatment option for high-risk malignant tumors affecting the epithelium of urinary bladder lining.

COMPLICATIONS AND MAIN ADVERSE EFFECTS OF Intravascular Therapy With DRUGS

Table 3 lists the most common adverse side effects related to the use of various compounds used in intravesical therapy. The symptoms and effects related to the use of BCG are the most frequently cited in the literature available in the state of the art, reflecting the fact that it is the most frequently used auxiliary therapy. (Table 3). Table 3 - Adverse Side Effects and j j

 } complications of the medicines used to

{intravesical bladder cancer treatment j 1

Medication j Side Effects | (%) l adverse patients) affected

I Cystitis> 50 j Fever (low grade) 25

] Prostatitis <5 i Bacillus Calmette-Guérin! Epididymitis <2

(BCG) i Fever (high grade) 3

 j Septicemia <0.5

1 Infection

 j generalized Rarely

Mitomycin CI Hematuria 10 I Myelosuppression

 j Skin Rash

 J Bladder contraction

 j Tissue necrosis

 j Chemical cystitis

 I Thiotepa j Myelosuppression

 s Chemical cystitis 25

1 Doxorubicin; Allergic reaction

References (Table 3): Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, Tl, and Tis): 2007 update. J Urol. 2007; 178 (6): 2314-2330 and Lamm DL, McGee WR, Hale K. Bladder cancer: current optimal intravesical treatment. Urol Nurs. 2005; 25 (5): 323-326,

331-332.

ADJUVANT IMMOTHERAPY WITH BCG - PRACTICAL PROBLEMS AND CONTRAINDICATIONS

 Although BCG vaccine used as a therapeutic adjunct in topical treatment of bladder cancer is the most effective state-of-the-art therapy available to prevent recurrence and tumor progression following urinary bladder cancer, a relatively large number of patients have recurrence and disease progression despite its use.

 BCG treatment is ineffective in about 30 to 40% of patients, and even in patients who have a good initial response to treatment, approximately 30% of them will relapse, ie, recurrence of cancerous lesions in the bladder epithelium after a given period. BCG time limit. For reference: Palou Redorta J. Management of BCG "Failures". Eur Urol.2006; 49: 779-80)

Additionally, the application of BCG vaccine in the intravesical treatment of bladder cancer is greatly hampered in practice by the occurrence of unwanted side effects, which are noted in about 90% of patients, which consist of irritative symptoms, presence of blood in the urination (hematuria). ), dysuria and urgency, leading to early discontinuation of treatment in many cases. For reference: (Perabo FG, Willert PL, Wirger A et al (2005) Preclinical evaluation of superantigen (Staphylococcal Enterotoxin B) in the intravesical immunotherapy of superficial bladder cancer. Int J Cancer 115: 591-598.) Episodes of infection, including systemic infection caused by the microorganism used (Mycobacterium bovis) in the preparation of BCG vaccine, require dose reduction, prolonged and costly antibiotic treatment and it is not uncommon to discontinue BCG treatment.

As already mentioned in this report, in a United States clinical study conducted in the year 2000 by the Southwest Oncology Group (SWOG 85071), due to unwanted side effects, only 16% of all patients who used intravesical BGC for treatment bladder cancer patients were able to complete the treatment. For reference, Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, Tl and transitional in situ carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000; 163: 1124-9.

 Finally according to the recommendations of the American Urolological Association (AU A) BCG vaccine is not recommended for use in the intravesical treatment of tumors in patients under the following conditions: a) In the two weeks following bladder surgery (TUR), b) in followed by traumatic bladder catheterization, c) in the presence of hematuria, d) in pregnant or breast-feeding patients, e) in immunosuppressed patients or on medication with immunodepressive effects, f) in patients receiving radiotherapy, g) in patients with a urinary tract infection and a history of allergy or who have experienced previous BCG reactions.

AUA recommendations on BCG vaccine use are: Guideline for the Management of Nonmuscle Invasive Bladder Cancer: (Stages Ta, Tl, and Tis): Update (2007) NON-SURGICAL OPTIONS FOR IMMUNOTHERAPY FAILURE WITH BCG-TECHNICAL STATE

 As stated, in the current state of the art, the effectiveness of the best available treatment for the treatment of urinary bladder cancer, which is the BCG vaccine, is lacking both by the high tumor recurrence rate and the occurrence of unwanted side effects, due to its high toxicity.

The high incidence of BCG-associated toxicity episodes undoubtedly preclude its widespread use as intravesical therapy for the treatment of all types of urinary bladder cancer after transurethral resection (TUR), leaving it as an option for treating the most aggressive types of tumors that affect this region.

 In the event of therapy failure using the BCG vaccine, including both tumor recurrence and treatment abandonment or definitive discontinuation following an episode of intolerable toxicity to the patient with tumor permanence, the most appropriate option in the state of the art is surgery for total or partial removal of the urinary bladder called cystectomy.

 It happens that this type of surgery is of high risk and invariably results in very significant deterioration in the quality of life for the patients, reason why it is sought to avoid or postpone it as much as possible.

 In the current state of the art, one of the possible options in case of failure of intravesical BCG therapy to prevent or delay total bladder removal (cystectomy) is its replacement in the intravesical treatment of urinary bladder lining epithelium with chemotherapeutic agents such as such as mitomycin C, thiotepa, adriamycin and others.

 Although the use of such chemotherapeutic agents may be considered a valid option for low-grade urinary bladder epithelial tumors, the same cannot be said for their use in patients with high-risk disease, ie, classified by the TNM System. in degrees, Ta, Tl, Tis.

 For example, in a study of 1,999 only 4 of 41 bladder cancer patients who failed to respond to intravesical BCG therapy who switched to intravesical chemotherapy (Mitomycin C) remained free of cancer recurrence during follow-up period. For reference: (Malmstrom PU, Wijkstrom H, Lundholm C, et al. 5-year follow-up of a randomized prospective study comparing mitomycin C and Calmette-Guerin bacillus in patients with superficial bladder carcinoma. J Urol 1999; 161.T 124-7 .

In summary, the use of intravesical chemotherapy in cancer using new compounds after failure of topical BCG therapy, whether due to relapse or abandonment of treatment with this vaccine, remains highly experimental and has not yet been able to provide same degree of therapeutic success with intravesical use of BCG vaccine. SOME EXPERIMENTAL THERAPIES FOR BLADDER CANCER AFTER BCG FAILURE

Photodynamic Therapy

 Photodynamic therapy comprises patients' oral ingestion of substances that will later be activated by light, such as 5-aminolevulinic acid (5-ALA) which will focus preferentially on tumor-affected epithelial tissues and a highly light source. (laser) for its activation.

The light is projected into the cavity of the organ to be treated by an appropriate device such as an instrument equipped with fiber optics capable of conducting light beams.

 Once fired in the organ cavity, light is captured and absorbed by the photosensitive substance, causing chemical transformation, which in turn releases toxic byproducts, capable of destroying the epithelium where the photosensitive substance is concentrated and eventually the tumors located in it.

Some clinical trials conducted with a small number of patients, including patients not responding to BCG therapy, have shown positive results that are reported in the state of the art. (Waidelich H, Stepp R, Baumgartner E, et al. Clinical experience with 5-aminolevulinic acid and photodynamic therapy for superficial refractory bladder cancer. J Urol 2001; 165: 1904-7.)

COMBINED IMMUNOTHERAPY (BCG + Interferon or Interleukin-2)

 In the state of the art, the most studied exogenous cytokine for joint application with BCG to increase its efficacy is interferon-alpha. In a clinical study of 1263 patients who had failed BCG therapy, they used the combination of both substances for intravesical bladder cancer treatment. For reference: O'Donnell MA, Lilli K, Leopold C. interim results from a national multicenter phase II trial of combination Bacillus Calmette-Guerin plus interferon alpha-2b for superficial bladder cancer. J Urol 2004; 172: 888-93.

Combination of the substances is necessary because the use of Interferon obtained from exogenous sources alone is not capable of producing therapeutic results when used for localized treatment of epithelial tumors in general and in the particular case of tumors originating from and located in the urinary bladder epithelium.

These patients treated with the combination of Interferon and BCG had their results compared with a group (control) that used only standard therapy, ie, BCG application alone. These control group patients, used for comparative purposes, did not have failure or intolerance to BCG application. Patients received a 6-week induction dose of BCG and Interferon, followed by booster doses at 3.9 and 15 months after dosing. induction

Results reported after approximately 2 years of patient follow-up show a disease-free percentage for 48% of patients treated with the BCG and Interferon combination. For reference: O'Donnell MA, Lilli K, Leopold C. interim results from a national multicenter phase II trial of combination Bacillus Calmette-Guerin plus interferon alpha-2b for superficial bladder cancer. J Urol 2004; 172: 888-93.

However, the control group treated with BCG alone (without episodes of failure) presented a percentage of absence of cancer for 60% of cases, with patients followed and analyzed in the same period of time. (O'Donnell MA, Lilli K, Leopold C. interim results from a national multicenter phase II trial of combination Bacillus Calmette-Guerin plus interferon alpha-2b for superficial bladder cancer. J Urol 2004; 172: 888-93). These results indicate that the combination of exogenous BCG and Interferon cannot overcome the efficacy of using the BCG vaccine alone in the treatment of urinary bladder epithelial cancer.

 Finally it should be noted that if the use of exogenous interferon alone is not reported in the prior art with significant therapeutic effects or free of toxicity against epithelial tumors in general and also in the particular case of tumors affecting the urinary epithelium, the combination Both substances are also unable to prevent BCG-related toxicity problems and thus have limitations on their use in practice.

 Likewise, the use of another exogenous cytokine, called Interleukin-2 (IL-2) as a BCG vaccine replacement drug, in the event of its failure, remains in experimental use and has not been reported in the state of the art to date. able to replace or have superior therapeutic effects to BCG vaccine in the treatment of bladder cancer. For reference, Giancarlo Pizza et al. Tumor regression after intralesional injection of interleukin 2 (IL-2) in bladder cancer. Preliminary report- International Journal of Cancer - DOI: 10.1002 / ijc.2910340312 SURGICAL TREATMENTS (CYSTECTOMY)

As already mentioned, in the current state of the art, the main therapeutic indication for patients not responding to the therapy of choice for bladder cancer, ie adjuvant intravesical treatment with BCG or chemotherapy after transurethral resection (TUR) is partial or total removal of the urinary bladder due to the high degree of risk of cancerous lesions progressing to more invasive forms.

This procedure is also indicated for patients who already present at the time of diagnosis the presence of invasive tumors (T2, T3, T4 - TNM System).

 Total or partial removal of the urinary bladder, called cystectomy, is a surgical procedure considered high risk and usually accompanied by a high degree of morbidity and mortality.

 In a study of 1054 patients who underwent radical cystectomy due to bladder cancer, almost all had postoperative complications of varying degrees, including complications of a severe nature and death associated with this type of surgery. For reference and example of the state of the art: Clark, Peter E. et al - Radical cystectomy in the elderly - Comparison of clinical outcomes between younger and older patients. Cancer-Volume 104, Issue 1, pages 36-43, 1 July 2005.

ALTERNATIVES FOR THE TREATMENT OF DISABLED PATIENTS FOR SURGICAL PROCEDURE.

 Due to the high probability of the occurrence of morbidity or postoperative complications, cystectomy is considered a high risk procedure and due to this fact a high percentage of patients are not in a position to undergo such surgery due to other pre-existing and / or age-associated medical conditions, such as heart problems, diabetes, and others.

For patients who do not respond to standard therapy, ie surgical removal of lesions followed by intravesical chemotherapy (eg, Adriamycin ...) or immunotherapeutic (BCG, Interferon, IL-12) therapy due to drug intolerance problems (BCG), failure to respond to therapy ie cancer recurrence, and additionally not able to undergo cystectomy, existing alternatives are limited to supportive measures, and the use of chemotherapy and radiotherapy in intravesical treatment and / or systemic to try to maximize the life of patients. For exemplary purposes: Toni K Choueiri and Derek Raghavan- Chemotherapy for muscle-invasive bladder cancer treated with definitive radiotherapy: persisting uncertainties- Nature Clinical Practice Oncology (2008) 5, 444-454.

NEED FOR NEW PRODUCTS AND THERAPIES Taking into account the noticeable shortcomings of current treatments for bladder cancer, such as surgical procedures (total or partial cystectomy, cryotherapy, laser), radiotherapy or drug therapies using chemotherapeutic compounds (eg Thiotepa, mitomycin C) or immunotherapeutic (BCG, exogenous interferons, IL-2), there is clearly a need for new treatment options for epithelial cancer treatment, including bladder cancer, that can replace or complement existing treatments, maximizing their efficiency.

 It would be highly desirable that these new treatments could be used without the occurrence of undesirable side effects, which are common in existing prior art treatments, as described in this report.

 The creative or inventive activity must be directed, therefore, to obtain new therapeutic modalities, including new methods and products, either alone or in association with each other and which in comparison are in practice superior to existing treatments in terms of efficacy and safety, ie , presenting less toxicity to the end user.

 The invention is surprisingly capable of providing an immunomodulatory compound for localized treatment of superficial epithelial tumors including those located in the urinary bladder epithelium, which has been shown to be used topically, alone or in combination with or associated with existing treatments by replacing or enhancing their effectiveness and at the same time without any occurrence of unwanted side effects.

 On the contrary, as will be shown in this report, with their combined use there has been a noticeable decrease in the frequency of unwanted side effects from other treatments.

 In order to arrive at the invention, a compound already known in the state of the art and described in PI-0305373-3, US 2006/0093628 Al, EP 1529784 Al was used, but using it in a manner totally different from its applications. known in the art, with surprising and unprecedented practical results, as will be detailed in detail through the descriptions and experiments provided in this report. The invention

It is well known in the art that the best available strategy for the treatment of tumors affecting the outer and inner lining epithelium is hereby. including urinary bladder tumors, is based on surgical excision of the tumor followed by adjuvant topical treatment to prevent recurrence of cancerous tumors or delay their multiplication and growth when complete eradication is not possible.

The use of compounds or medicaments in the intravesical treatment of tumors located on the outer and inner lining epithelium in topical application form is facilitated by the relatively unobstructed access of such anatomical regions as, for example, to the skin and hollow organs such as urinary bladder.

This anatomical feature allows access to the topical application of compounds capable of exerting a localized effect, that is, acting through direct or topical contact between the therapeutic agent and the affected region, since the tissue or region of interest can be reached to drug or compound deposition using various specialized techniques or equipment for such function, such as catheters and probes.

It should also be borne in mind that this type of tissue, being poorly irrigated, makes it difficult or even impossible for therapeutic substances that depend on their transport to reach the most superficial layer of the epithelium, increasing the importance of topical treatment for action. curatively or palliatively in this special type of fabric.

Finally, local drug delivery aims to obtain the maximum contact and the highest possible concentration between the therapeutic agent and the most superficial epithelial surface where the tumors are located.

 Taking into account, therefore, the possibility of access to such regions and the poverty or lack of blood supply in these regions, the selection or use of compounds capable of exerting a localized effect is of fundamental importance for the invention or availability of new treatments against malignant lesions. or premalignant located on the outer and / or inner lining epithelium.

For example, the treatment of tumors in the intravesical lining epithelium takes advantage of the fact that the anatomy of the organ allows access from outside to introduce drugs or solutions containing them through the use of catheters or probes that penetrate the organ through the urethra, and by this way obtaining access to the internal space of the urinary bladder. This type of application, that is, direct or topical application of drugs to organs with cavities or interior spaces, can be and is routinely used to treat cancerous tumors in the epithelium lining of organs other than the bladder. such as the stomach or esophagus.

 In view of such particularities and problems cited and for the purposes of the invention, i.e. providing a new and effective therapeutic agent capable of topically acting on the inner and outer lining epithelium required a compound having the following Capacities or properties:

(A) capable of being used for therapeutic purposes against malignant or premalignant lesions situated on both the inner lining epithelium and the outer lining epithelium;

 (B) capable of having a therapeutic effect individually or in combination with other treatments, whether medicated or non-medicated,

C) Did not present no relevant toxic effects and / or minimized toxic effects from other treatments.

 The invention enables all of these requirements to be met in an integrated manner, namely, the above-mentioned items A, B and C.

 The invention was arrived at by obtaining surprising new scientific data from experiments involving the comparative evaluation of cancer treatments affecting the lining epithelium, including the urinary bladder.

 These experiments of therapeutic effect involved the comparison in animal models and human studies of several compounds already known in the art and among them the BCG vaccine, the mitomycin C chemotherapeutic and the biological response modifier called phospholinoleate anhydride protein aggregate. ammonium magnesium palmitoleate described in the state of the art in PI -

0305373-3, US 2006/0093628 Al, EP 1529784 Al.

Analysis of the data from these experiments and scientific studies has revealed totally novel biological and therapeutic effects and properties in the state of the art for the compound called the ammonium magnesium phospholineate palmitoleate anhydride protein aggregate, which were used for the elaboration of the present invention. It has been found in practice that when tested by direct or topical contact in cancer-bearing epithelial tissues, the immunomodulator or biological response modifier (ammonium phospholineate palmitoleate anhydride protein aggregate -PI - 0305373-3, US 2006/0093628 Al, EP 1529784 Al) In an unprecedented and surprising way, it was also shown to be capable of direct action, that is, acting by simple contact in the epithelial region where the cancerous lesion is located.

This unprecedented property, hitherto unknown for the aforementioned compound (ammonium phospholinoleate palmitoleate anhydride protein aggregate - PI - 0305373-3, US 2006/0093628 Al, EP 1529784 AL), ie its previously unknown capacity prior art, to exert therapeutic action by simple contact with the affected region, represents one of the reasons for its use in the invention, ie as a topical medication for treating malignant or premalignant lesions affecting the outer lining epithelium or internal.

 In addition the compound cited (Ammonium and Magnesium Phospholinoleate Palmitoleate Anhydride Protein Aggregate - PI - 0305373-3, US 2006/0093628 Al, EP 1529784 Al) was far superior to existing drug therapies and most surprisingly and yet unprecedentedly , not only increased its effect when used together, also in the form of topical application, but also decreased the toxicity of the treatment to the end user, being added these remarkable and unprecedented practical advantages of its use for the purposes of the invention. In other words, this novel ability to act locally or topically on the inner and / or outer lining epithelium, and without toxicity to the treated epithelium, makes it available as adjuvant therapy for the topical treatment of malignant and premalignant lesions. alone or in conjunction with other therapies and procedures, with advantages over what has been known hitherto in the art.

To date, it was known and reported in the prior art (PI - 0305373-3 US 2006/0093628 Al, EP 1529784 Al) that the immunomodulatory compound (ammonium phospholinoleate palmitoleate anhydride protein aggregate) was associated antirumor activity only when used systemically and for this purpose should be introduced into the body by subcutaneous, intramuscular and intraperitoneal application. In fact, in PI-0305373-3 US 2006/0093628 Al, EP 1529784 Ale in other references in the state of the art it is reported in the state of the art that the immunomodulatory compound (ammonium phospholineate-palmitoleate anhydride protein aggregate.) It only has therapeutic action when used systemically and for this depends on its introduction by injection into the body to be able to act through activation of the immune system.

 Therefore the performance of this compound has always been through its systemic use and the best strategy for treating superficial bladder tumor as well as other tumors affecting the lining epithelium, in the current state of the art, requires that after surgical removal of the bladder topical treatment to prevent recurrence of cancerous tumors.

 And the performance of compounds that act systemically and / or depend on internal transport routes such as the venous or lymphatic system is ineffective in treating malignant or premalignant lesions located on the inner and outer lining epithelium, because these regions are poorly irrigated.

 Additionally the compound (Ammonium and Magnesium Phospholinoleate Palmitoleate Anhydride Protein Aggregate - PI - 0305373-3, US 2006/0093628 Al, EP 1529784 Al) has always been innocuous or ineffective when employed against cancer cells in vitro or in other However, to date, it has been shown to be ineffective for action through contact with the tumor cell, and is thus reported in the state of the art.

(PI - 0305373-3, US 2006/0093628 Al, EP 1529784 Al): "Cytotoxic properties: The cytotoxicity of the compound of the present invention has been studied in the concentration range of 0 ^{~ 4} to 10 ^{~ 8} M in 53 types of cultured tumor cell lines representing 8 different tumor types (lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer). present invention did not show cytotoxicity to these tumor cells. "See excerpt in: PI - 0305373-3

It is also quoted in the English language "Cytotoxic properties. Cytotoxicity of the compound of the present invention was studied in the range of 10 ^{~ 4} to 10 ^~ 8M in 53 tumor cell cultures representing 8 distinct tumor types (lung, colon, central nervous system, melanoma, ovary, kidney, prostate and mammary) and leukemia. present invention did not display cytotoxicity for these tumor cells. "(US 2006/0093628 ΑΙ, ΕΡ 1529784 Al)

 Therefore and most surprisingly the immunomodulator (ammonium phospholinoleate palmitoleate anhydride protein aggregate PI - 0305373-3, US 2006/0093628 Al, EP 1529784 Al) which has so far been reported in the state of the art in these publications and others as acting against bacterial and viral infections and even against cancer, but always requiring their use systemically to have positive effects against diseases, now when used topically for the purposes of the invention, has also shown potent therapeutic effects, making them available. if so new and unprecedented applications for this compound, described in this report.

 That is, when used in animals and humans the compound (ammonium phospholinoleate-palmitoleate anhydride protein aggregate PI - 0305373-3, US 2006/0093628 Al, EP 1529784 Al.) Has now been shown to be able to act as well. topically.

 The compound in question was able to act therapeutically by simply contacting the product with the injured epithelial tissue, for example as it was introduced into the bladder via a catheter, added to a saline suspension or even when formulated as creams. for topical use on the skin as described including examples of practical use in this report.

 These results are totally unpublished and surprising since all the scientific literature data reported in the state of the art so far only provided indications that the product (ammonium phosphololeate palmitoleate anhydride protein aggregate PI - 0305373-3 US 2006/0093628 Al, EP 1529784 Al) only acted against cancer in a systemic way, acting indirectly by mobilizing an immune response from the organism, caused after the introduction of the compound by injection.

And most surprisingly, as will be shown in this report by examples of practical use, when used for the purposes of the invention the ammonium phospholinoleate palmitoleate anhydride protein aggregate compound (PI - 0305373-3, US 2006/0093628 Al, EP 1529784 Al) proved to be more effective than the best state-of-the-art topical treatment available for superficial urinary bladder cancer, which is the BCG vaccine. (Table-4) Finally and also surprisingly, it showed no adverse side effects on the internal mucosa (epithelium) of the organ when compared to state-of-the-art advanced intravesical drugs for the treatment of high-risk bladder cancer (Ta, Tl, Cis), which is the BCG vaccine. (Table -4) While all BCG-treated urinary bladder cancer animals had urinary bleeding or post-treatment hematuria, animals treated with the immunomodulator alone showed no signs of urinary bleeding. Microscopic examinations of the tissues of the treated animals revealed only characteristic signs of reversal of the tumor process. (Table 4).

Reversal of the tumor process, ie curative therapeutic effect, occurred when the compound of the invention was used alone and also when used in combination with other compounds to treat urinary bladder cancer, increasing the therapeutic efficacy of the combination (synergy). This is proven using an animal model (Table 5).

In this particular aspect, that is, when combined with other drugs, such as BCG and Mitomycin C, the use of the invention has not only been able to provide a synergistic effect against cancerous lesions, but more surprisingly has reduced the associated toxicity. treatment with these other medicines (hematuria) for animals in the experiments (Table 5 and Table 6)) Reversal of precancerous and cancerous lesions on the outer lining epithelium (skin) is also sufficiently demonstrated at present for a skilled practitioner to In the prior art, it is readily appreciated that the invention can without any hindrance be used in the treatment of malignant or premalignant lesions of this specific anatomical region. (Tables 7 and Tables 8-A and 8-B)

OBJECTIVES OF THE INVENTION

 Accordingly, it is an object of the present invention to provide a compound for the topical adjuvant treatment of malignant and premalignant lesions located on the inner and outer lining epithelium.

It is a further object of the invention to provide a compound for use also in conjunction with other therapeutic modalities for the topical treatment of malignant lesions within the inner and outer lining epithelium, whether medicated or non-medicated. It is also an object of the present invention to provide a novel means of drug treatment which has been shown to be superior to drugs used in the state of the art for the topical treatment of malignant lesions in the inner and outer lining epithelium.

It is an object of the present invention to provide a novel and potent treatment medium capable of providing an additive (synergistic) therapeutic effect when used with other prior art drugs for the topical treatment of malignant lesions in the inner and outer lining epithelium. .

 It is a further object of the present invention to provide a novel drug treatment medium without relevant toxicity to users as compared to prior art drugs intended for the topical treatment of malignant lesions located on the inner and outer lining epithelium.

 Additionally, it is a further object of the present invention to provide a novel and potent treatment medium capable of enabling an additive (synergistic) therapeutic effect when used with other prior art drugs for the topical treatment of malignant lesions located in the epithelium of internal and external coating and simultaneously decrease the toxicity of treatment with the other compounds to users.

 It is also an object of the present invention to provide a potent new means of treatment capable of substituting drug treatments, particularly the BCG vaccine when used in the topical treatment of malignant lesions in the lining epithelium, when the BCG vaccine has no therapeutic effect. satisfactory or needs to be replaced by problems related to unacceptable or intolerable toxicity to users.

It is an object of the present invention to provide a novel means of palliative treatment against malignant lesions in cases where excisional surgery or other destructive treatment modalities of the lesions are not feasible for reasons of unacceptable medical risk to patients.

Finally, it is an object of the present invention to provide two methods of providing the product or pharmaceutical formulation for end use, in solution and cream form for topical application, and to indicate other possible methods for their practical use. And to sufficiently demonstrate the properties and comparative advantages of the invention over existing products in the prior art, examples of its practical use are given below.

 These experiments of practical use of the invention and their results are detailed below in the present report, by way of explanation only to highlight the inventive activity, absolute novelty and comparative utilities and advantages of the invention and may not be used at any time to restrict the invention or its field of application.

 Without the need for further information, it can be stated that anyone skilled in the art, with the aid of only the information and examples of practical use to be provided herein, will be able to understand and use the invention to its fullest extent. .

 Although the invention is intended for human use, there is nothing to prevent it from being used also in the treatment of malignant or premalignant lesions in animals which are also possessing lining epithelial tissue and also subject to the occurrence of tumors in these anatomical regions.

 PRACTICAL EXAMPLE OF USE OF THE INVENTION IN THE TREATMENT OF BLADDER CANCER COMPARATIVE WITH THE BGC VACCINE EXPERIMENT Objective: To compare the therapeutic response in animals undergoing experimental induction of bladder cancer using n-methyl-n- nitrosourea (MNU)

 Forty animals (n = 40) were used in the experiment.

 Of these, 30 animals were submitted to 1.5 mg / kg of n-methyl-n-nitrosourea (MNU) dissolved in 0.30 ml of sodium citrate intravesically using a catheter for 7 weeks. One group (control) of 10 animals received only physiological solution (NaCl 0.90,%) by the same route and for the same period.

The purpose of the application of n-methyl-n-nitrosourea (MNU) is the experimental induction of immunosuppression and subsequent production of urinary bladder carcinoma. After treatment with MNU the animals were divided into 04 groups of 10 animals each. After using MNU for 7 weeks, 3 batches of 10 animals each were subsequently subjected to intravesical inoculation of 0.30 ml 0.9% saline (control group), 10 ⁶ CFU (40 mg) BCG intravesically and 10 mg / kg of the immunomodulator (phospholinoleate palmitoleate anhydride protein aggregate of ammonium and magnesium PI - 0305373-3, US 2006/0093628 A1, EP 1529784 A1), suspended in saline using a catheter for 14 weeks.

 After this procedure 10 animals from each group were sacrificed and their urinary bladders removed to collect tissue fragments, which were included in histological paraffin and prepared for histological sectioning by the usual techniques.

For histological examinations these fragments of urinary bladder tissue were cut in Zeiss microtome, resulting in 2 μ ^η ι pieces mounted on slides for microscopy, and stained by the hematoxylin-eosin (HE) technique, which were finally submitted for evaluation. by a pathologist, for verification and quantification of cellular alterations and comparison between the control group and treated groups.

 Finally, the treated and untreated animals had their blood collected at the end of the experiment, processed and the plasma obtained by separation was completely digested using acids (H2OS04 and HN03) concentrated and subjected to Mg ++ quantity evaluation techniques. which is the major inorganic component of the molecule (ammonium phospholinoleate palmitoleate anhydride protein aggregate) by atomic absorption to verify and quantify a possible systemic absorption of the compound of the invention from the lining epithelial tissue (Table 4 )

RESULTS

 The therapeutic effect, as assessed by histological as well as toxicological effect, measured by the presence or absence of hematuria for topical use of the compounds (ammonium phospholineate palmitoleate anhydride protein aggregate PI - 0305373-3, US 2006 / 0093628 Al, EP 1529784 Al- Group D - Table 4) and BCG (Group C-Table 4) and the results are shown in Table 4.

Table 4 Group A Group B Group C Group D

Evaluation (non-control (MNU) (BCG) (Treated histological anhydride) polymeric) n = 10 n = 10 n = 10 n = 10

 Hyperplasia - - - 06 (60%) Flat

 Hyperplasia - 01 = 10% 0 = 40% 02 = 20% Papillary

 Carcinoma 03 = 0%

intraepithelial

low grade

Carcinoma - 03 = 30% 02 = 20% -

RESULTS DISCUSSION - TABLE 4

 The use of the compound of the present invention (ammonium phospholinoleate-palmitoleate anhydride protein aggregate) in terms of therapeutic effect in the practical example, ie treatment of cancer induced in MNU mice was much superior to the best available therapy (BCG ) used in the state of the art for postoperative adjunctive treatment of malignant urinary bladder epithelial lesions. This therapeutic effect has been evaluated for all compounds used, whether from therapies through histopathological analysis of urinary bladder epithelial tissue. (Table 4)

 A positive result was experimentally observed for 80% of the animals treated with the compound of the invention, ie the ammonium phospholinoleate palmitoleate anhydride protein aggregate (Table 4 - Group D), with 20% of animals presented with completely normalized tissue and 60% of the animals presented only flat hyperplasia and 20% presented papillary hyperplasia. Flat hyperplasia and papillary hyperplasia are inflammatory but benign reactionary changes, and their presence in the results of the experiment clearly indicates a reversal of the cancerous process to noncancerous stages.

Comparatively, the use of the BGC vaccine was positive for 40% of the animals (Table 4-Group C) that had papillary hyperplasia, while 20% of the treated animals still had low grade carcinoma and 20% had high grade carcinoma. (in situ carcinoma (Tis) - TNM classification) and 10% of the animals presenting squamous metaplasia (Table 4 - Group C). Metaplasia is defined as the replacement of normal functional tissue with a differentiated tissue with loss of function and is therefore considered a form of precancerous lesion.

 Referring to the quantitative determination of Mg ++ in plasma, it was observed that quantitative evaluation of Mg ++ ions, which is the main inorganic component of the compound of the invention measured in the plasma of untreated control animals (Group A - Table 7). and the treated group (group D - Table 7) was the same, ie 34.6 ± 5.1 µg / mL. This data shows that there was no systemic absorption of the compound of the invention (ammonium phospholinoleate palmitoleate anhydride protein aggregate).

 Non-penetration beyond the epithelial layer is possibly linked to the relatively large size of the molecule which is indicated by its high molecular weight of 420,000 Dalton (420 kDa), which also demonstrates that the anti-tumor biological and therapeutic effect of immunomodulator (ammonium and magnesium phospholinoleate palmitoleate anhydride protein aggregate) in this case is due to a local effect on the coating epithelium.

 Finally, it is observed that of the animals treated with the carcinogenic compound MNU (Table 4 - group B) almost all (90%) presented cancerous lesions, being 60% with papillary carcinoma (Ta - TNM classification) and 30% carcinoma in situ. (Tis-Classification TNM), indicating that the compound in question (MNU) is highly effective in inducing experimental cancerous lesions.

It should be noted that the result of using a carcinogenic compound such as MNU in the animal model for cancer study bears a striking resemblance to what occurs in practice in humans, as it is known in the art that bladder cancer is associated with chronic action of aggressive chemical agents in the urinary bladder.

 These aggressive chemical agents are introduced or generated in the body of humans as a result of smoking and the consumption of alcohol.

Finally it may be thought that a hypothetical mechanism of action for the remarkable effect observed in the topical treatment of bladder cancer for the use of the invention would be an action of the compound (ammonium and magnesium phospholinoleate palmitoleate anhydride protein aggregate) similar to that of BCG vaccine, also used in the experiment for comparison purposes (Table-4). It is a well-established fact in the art that BCG vaccine when used topically in the intravesical treatment of bladder cancer is known to be able to mobilize a potent immune response by activating antigen presenting cells (APCs) such as cells. dendritic cells, which are present in the inner and outer lining epithelium.

 But the absolute utility or novelty of the invention does not depend on the establishment or description of its possible mechanisms of action, since the invention is intended for practical purposes.

Toxicology:

Animals treated with the invention: None of the animals used in the experiment using the compound of the present invention, namely the immunomodulator (Ammonium Phospholinoleate Palmitoleate Anhydride Protein Aggregate - PI - 0305373-3, US 2006/0093628 Al , EP 1529784 Al) in continuous application presented (Group D - Table 4) showed signs of the presence of blood in the urine also called hematuria.

BCG-treated animals: All BCG-treated animals had blood expelled through the urine (hematuria). Hematuria in these animals ranged from moderate (80%) to severe (20%) in response to continued application of intravesical BCG from ^the second week. (Group C - Table 4)

Hematuria was used in all experiments involving the use of the invention in the treatment of bladder tumor as the most obvious sign and parameter for assessing the local toxicity of the compounds used, as it is related to irritation or chronic inflammation of the affected tissue caused by chemical agents, in this case the urinary bladder lining tissues.

Therefore, the use of the present invention in practice is also more effective than immunotherapy using BCG when considering toxicity, as the result of the hands-on experiment has undoubtedly shown that the use of the invention did not result in any sign of toxicity to the drug. epithelium (Group D-Table 4) when compared with BCG, (Group C-Table 4) for equal time periods and using the same route of administration, ie the intravesical route.

Accordingly and surprisingly the compound which is the object of the present invention ammonium phospholinoleate palmitoleate anhydride protein aggregate (PI - 0305373-3, US 2006/0093628 Al, EP 1529784 Al.) Is not only shown capable of topical action, which is unheard of in the state of the art, as it still proves superior to the treatment of bladder cancer than the best treatment hitherto available in the state of the art, namely the BCG vaccine.

 Therapeutic and toxicologically superior BCGs represent surprising and unprecedented effects or properties in the prior art for the compound of the present invention (ammonium phospholinoleate palmitoleate anhydride protein aggregate - PI - 0305373-3, US 2006/0093628 (EP 1529784 A1).

 PRACTICAL SECOND EXPERIMENT OF USE OF THIS INVENTION COMPARED TO CHEMORATORY MEDICINAL PRODUCTS IN TREATMENT OF BLADDER CANCER - (TABLE- 5)

 Forty animals (n = 40) were used in the experiment.

 Therapeutic effect was evaluated by histological evaluation of tissues and the toxicological effect of compounds by evaluating the presence or absence of urinary bleeding also called hematuria. Results are shown in Table 5.

 In this experiment the compounds, ammonium and magnesium phospholinoleate palmitoleate anhydride (PI - 0305373-3, US 2006/0093628 Al, EP 1529784 Al) and Mitomycin C compounds were used for comparative evaluation in the treatment of MNU-induced cancerous lesions. .

 All animals were submitted to 1.5 mg / kg of n-methyl-n-nitrosourea (MNU) dissolved in 0.30 mL of sodium citrate intravesically using a catheter for 7 weeks. One group (control) of 10 animals received only physiological solution (NaCl 0,%) by the same route and for the same period.

The purpose of the application of n-methyl-n-nitrosourea (MNU) is the experimental induction of immunosuppression and subsequent production of urinary bladder carcinoma. After treatment with MNU the animals were divided into 04 groups of 10 animals each. Following the use of MNU for 7 weeks, 3 batches of 10 animals each were subsequently subjected to intravesical inoculation of 0.30 ml 0.9% saline (control group), 10 mg / kg of mitomycin C suspended chemotherapy. in sterile water for injection and 10 mg / kg of the ammonium magnesium phospholinoleate palmitoleate anhydride protein aggregate (PI - 0305373-3, US 2006/0093628 Al, EP 1529784 Al), suspended in saline solution, using a catheter for application of all substances for 14 weeks.

 After this procedure, all 10 animals from each group were sacrificed and their urinary bladders removed to collect tissue fragments, which were included in histological paraffin and prepared for histological sectioning by the usual techniques.

For histological examinations these fragments of urinary bladder tissue were cut in Zeiss microtome, resulting in 2 μι ^η pieces mounted on slides for microscopy and stained by the hematoxylin-eosin (HE) technique.

For histological examinations these fragments of urinary bladder tissue were cut in Zeiss microtome, resulting in 2 μι ^η pieces mounted on slides for microscopy, and stained by the hematoxylin-eosin (HE) technique, which were finally submitted to evaluation by professional pathologist, for verification and quantification of cellular alterations and comparison between the control group and treated groups.

 Comparative therapeutic and toxicological results between the use of the invention and mitomycin C are shown in Table 5 below.

RESULTS DISCUSSION - TABLE 5

 By evaluating the data in Table-5 it is clear that the use of the biological response modifier (ammonium phospholinoleate palmitoleate anhydride protein aggregate) alone, topically applied, ie directly applied (intravesically) in the urinary bladder-lining epithelial tissue that was stricken with cancer resulted in a much higher therapeutic effect, either in terms of tumor response or lower toxicity (Group D - Table 5) compared with group treated with compound Mitomycin C (Group C-Table 5).

While the group treated with Mitomycin C had 10% of animals within normal parameters, 40% with papillary hyperplasia and 50% still with cancer (group C-Table -5) the group treated with intravesical topical application using the invention, had 30%. animals within normal parameters and 70% with cell classification described as hyperplastic. (Group D-Table 5).

Since hyperplasia is a noncancerous cell form, it is concluded from the experiment reported in Table 5 that the invention had a therapeutic efficacy of practically 100% (70% for hyperplasia and 30% for normality) compared to control animals (Group B-table 5) that presented 90% of the animals with cancer (30% classified as Tis-in situ tumor and 60% as Ta-papillary carcinoma). Mitomycin C (Group C-Table 5) was 40% effective (papillary hyperplasia) and 50% of the animals with cancer (30% low grade carcinoma and 20% with in situ Tis tumor), with only 10%. % of animals within normal parameters (Group C-Table 5).

 Regarding toxicology it is immediately apparent that the use of the compound of the invention did not result in any indication of local toxicity (Group D-Table 5), as none of the treated animals showed urinary bleeding (Group D-Table 5), whereas animals that received used Mitomycin C showed 100% positivity for the presence of hematuria (group C-table 5).

 THIRD PRACTICAL EXPERIMENT - ASSESSMENT OF THE COMBINED USE OF INVENTION WITH CHEMOTHERAPIC AND IMMUNOTHERAPIC TREATMENT - TABLE 6

Seventy animals (n = 70) were used in the experiment. In this experiment we used the ammonium phospholinoleate-palmitoleate anhydride protein aggregate compounds 10 mg / kg), BCG (10 ⁶ CFU (40 mg)) and Mitomycin C (10 mg / kg) applied intravesically for comparative treatment evaluation. of MNU-induced cancerous lesions.

 All animals except the untreated control group (n = 10) underwent 1.5 mg / kg of n-methyl-n-nitrosourea (MNU) dissolved in 0.30 ml of sodium citrate. intravesically using a catheter for 7 weeks. One group (untreated control) of 10 animals received only physiological solution (0.9% NaCl) by the same route and for the same period.

The purpose of the application of n-methyl-n-nitrosourea (MNU) is the experimental induction of immunosuppression and subsequent production of urinary bladder carcinoma. After treatment with MNU the animals were divided into 06 groups of 10 animals each. Following the use of MNU for 6 weeks, the 5 lots of 10 animals each were subsequently all subjected to intravesical inoculation of the compounds of interest for 8 weeks.

The groups were divided as follows: Group A (untreated control) received only saline (0.9% NaCl) for 8 weeks, group B received only MNU and 0.9% saline, group C received 10mg / kg of the compound of the invention (Ammonium-Magnesium Phospholinoleate Polymeric Anhydride-10 mg / kg) for 8 weeks, intravesically, group D received BCG vaccine (10 ⁶ CFU (40 mg)) for 4 followed by application of the compound of the present invention (Ammonium-Magnesium Phospholinoleate Polymeric Anhydride - 1 Omg / kg) for a further 4 weeks.

Group E received mitomycin C (10 mg / kg) for 4 weeks, followed by application of the compound of the present invention (ammonium phospholinoleate palmitoleate anhydride protein aggregate 10 mg / kg) for a further 4 weeks, group F received BCG vaccine (10 ⁶ CFU (40 mg)) for 8 weeks and group G received mitomycin C (10 mg / kg) for 8 weeks.

All compounds were administered to animals intravesically using appropriate diluents already described in this report. For better viewing purposes see the following table which is called Experimental Groups.

After these procedures, and at the end of the experiment all 10 animals from each group were sacrificed and their urinary bladders removed to collect tissue fragments, which were included in histological paraffin and prepared for histological sectioning by the usual techniques.

 For histological examinations, these fragments of urinary bladder tissue were cut in Zeiss microtome, resulting in 2 μιη pieces mounted on microscopic slides and stained by the hematoxylin-eosin (HE) technique.

 For histological examinations these fragments of urinary bladder tissue were cut in Zeiss microtome, resulting in 2 μηι pieces mounted on slides for microscopy, and stained by the hematoxylin-eosin (HE) technique, which were finally submitted to professional evaluation. pathologist, for verification and quantification of cellular alterations and comparison between the control group and treated groups.

Comparative results of using the compound of the invention used in conjunction with other compounds and compared to the isolated results for each compound are shown in Table-6.

TABLE 6 - DISCUSSION OF RESULTS By analyzing the data in Table-6 it can be clearly seen that not only the use of the invention in the form of topical intravesical application associated with other drugs (Mitomycin C and BCG vaccine) showed synergistic effects (Group D and group E - Table 6), as it still allows to see that in fact the invention allows the substitution of these drugs in case of their failure or appearance of side effects impeding their use, which in the case of BCG vaccine and Mitomycin C It is a fairly common occurrence.

It is further noted that the use of the invention notably contributes to the reduction of local toxic effect (haematuria) when used in combination with Mitomycin C and BCG vaccine (group D and group E-table -6). These data regarding the practical use of the invention, notably the synergy of effect with other drugs and the reduction of toxic effect for the combination, also show its practical use, ie used for protocols combined with chemotherapy and immunotherapy in topical treatment. of internal and external epithelium cancer (Table -6- Groups D and Group E)

 These data regarding the practical use of the invention, notably the synergy of effect with other drugs and the reduction of toxic effect for the combination, also allow to visualize its practical use for the merely palliative treatment of cancer cases affecting internal lining epithelium. , especially urinary bladder and uterus, when surgical treatments are not feasible due to medical problems related to the high probability of unacceptable morbidity and / or high mortality risk (Table -6).

 CANCER IN EXTERNAL COATING EPITHELIUM - SKIN CANCER - STATE OF THE TECHNIQUE

Introduction

 Skin cancer, like any cancer, is a disordered growth of cells that have the potential to spread or deepen into other organs, which usually occurs if such lesions are not detected and treated in time.

Skin cancer can be attributed to several factors, one of the main long periods of exposure to intense ultraviolet rays from solar radiation. It is considered the most common type of cancer, accounting for about 25% of all neoplastic lesions.

 Other causes include prolonged exposure to chemicals, especially the action of some types of viruses such as papilloma or HPV, genetic factors and ultimately low immunity.

 In relation to papillomavirus (HPV) viruses these agents are related as causes of potentially malignant transformations, also called cellular dysplasias in the outer or inner lining epithelium.

Papillomaviruses also called human papillomavirus or HPV cause various types of clinical manifestations such as skin warts, genital warts and finally premalignant cellular changes (dysplasias) in the epithelium. cervical lining, which can often develop into cancer if left untreated.

 In the prior art the treatment adopted for HPV virus lesions in the outer lining epithelium (skin) is the destructive or excisional treatment of the lesions using surgical means such as chemoabrasion, laser removal surgery, cryocauterization, example. However, merely exceptional or destructive treatment of the affected tissue is not alone capable of preventing tumor recurrence or virus-caused lesions on most occasions, forcing the use of combined therapies.

With the advancement of the state of the art, some new drugs, notably immunomodulatory drugs with Interferons and the biological response modifying compound called Imiquimod, are now being used for topical adjuvant therapy against HPV skin forms, associated or preceded by previous removal procedures. injuries.

Generally speaking, it can be said that the choice of treatment type for precancerous or cancerous lesions will depend on the type of cancer, the location of the cancer, the age of the patient, and finally whether the cancer is primary or a relapsed lesion.

 In the case of cancer already manifested or diagnosed, treatment usually begins by surgical removal of the lesions by various techniques such as chemoabrasion, laser removal surgery, cryocauterization, etc., followed by radiotherapy or topical chemotherapy.

 For example, surgery followed by topical chemotherapy may be indicated for the treatment of superficial large basal cell carcinoma.

 For low-risk tumors, external radiotherapy or topical chemotherapy using compounds such as imiquimod, resiquimod and the compound called 5-fluorouracil, and other procedures such as cryotherapy may provide adequate treatment of the disease.

Other treatment modalities such as photodynamic therapy employing compounds that activate with polarized light or laser may also be employed in conjunction with excisional lesion surgery. Other more aggressive epithelial tumors such as melanoma, which is considered the most lethal type of skin cancer, are poorly sensitive to radiation or chemotherapy, but can be successfully countered by combining surgical removal of the lesions, followed by the application of topical or systemic immunotherapy, especially if malignant or premalignant lesions are detected early.

 In summary, it is well established in the art to understand that the best treatment for malignant or premalignant lesions affecting the outer lining epithelium (skin) should use a combination of therapies, primarily those capable of localized or topical action, to greater therapeutic efficacy, including minimization of relapse.

 The same understanding applies to malignant or premalignant lesions affecting the inner lining epithelium, such as bladder cancer and uterine lesions caused by various types of HPV.

The present invention, because of the surprising new functionalities of the imnomodulator (ammonium phospholinoleate palmitoleate anhydride protein aggregate), is especially suited to fulfill these requirements and also represents a new and important advance in the state of the art for treatment. topic of malignant lesions located on the outer and inner lining epithelium.

 By way of example, here are two examples of the practical use of the invention in the localized (topical) treatment of HPV-like lesions associated with the outer (skin) and inner (uterus) lining epithelium.

 These practical examples are given for explanatory purposes only and are not intended to diminish or limit the scope or scope of the invention.

The results obtained in these hands-on experiments, in addition to indicating the efficacy of the invention in these specific diseases, can be extrapolated to show the utility of the invention also for other situations where localized treatment against cancerous or precancerous lesions located on the epithelium may be required. external and internal. PRACTICAL USE EXAMPLE NUMBER - USE OF THE INVENTION FOR THE TYPICAL TREATMENT OF VIRUS-Associated HPV - TABLE- 7

 Ten male volunteers with superficial wart-shaped lesions on the penile skin epithelium, clinically diagnosed as acuminate condyloma, usually associated with HPV, were selected.

All patients were admitted to the lesion relapse trial after excisional pretreatment using topically applied podophyllin on and around the external genital warts.

Laboratory examinations of tissue samples taken from lesions of all lesion carriers previously analyzed by the in situ hybridization technique were all positive for HPV, confirming the clinical diagnosis of HPV-associated acuminate condyloma condyloma.

 Of the 10 volunteer patients, 6 (patients 1, 2, 3, 4, 5 and 6) underwent excisional removal of the genital warts using topical application of podophyllin in the affected regions for 4 days, giving an interval of 2 days, followed by daily topical application to each patient of the compound of the present invention (ammonium phospholinoleate palmitoleate anhydride protein aggregate) suspended in an appropriate vehicle (topical cream-pH 7) consisting of sterile vaseline and water sterile and deionized distillate with 15% concentration of active compound (ammonium phospholinoleate palmitoleate anhydride protein aggregate) for a further 4 days.

 Of the 10 volunteers, 4 (patients 7, 8, 9, 10) underwent previous treatment only, ie, new excisional removal of genital warts using topical application of podophylline for a total of 8 days without subsequent use of the compound of the present invention.

 Participants were followed for an additional 30 days to check for possible recurrence of lesions.

 RESULTS

The results were remarkable and surprising for the topical use of the compound of the present invention. Of the patients who used the combined treatment (patients number 1, 2, 3, 4, 5, 6), only patient 2 presented recurrence of lesions, ie, new recurrence of lesions (warts or condyloma) in the penile region. Post-treatment laboratory examination (in situ hybridization) of this patient (patient 2) was positive for HPV.

 All other patients (patients 1, 3, 4, 5,6) presented no recurrence of lesions (warts or condyloma) in the post-clinical clinical and laboratory follow-up.

 Non-relapsing patients using the compound of the present invention (patients 1, 3, 4, 5,6) were also negative for the presence of HPV in the specific laboratory examination (in situ hybridization).

 All patients using podophyllin alone (patients 7, 8, 9,10) were positive for the presence of new recurrence of lesions (warts or condyloma) associated with the residual presence of HPV virus detected by specific laboratory examination (hybridization). in situ).

DISCUSSION OF TABLE RESULTS 7

 It can be concluded that the use of the compound of the present invention used in the epithelium as a topical application has a clinical and laboratory efficacy of approximately 90% (Table -7), which undoubtedly represents a remarkable gain in efficacy over a of the main types of treatment practiced in the state of the art for localized treatment of this type of lesion associated with the presence and performance of the HPV virus.

Although injury removal (warts or condylomas) has been used after podophilin chemoabrasion, nothing prevents the invention from being used in combination. with other therapies or techniques such as, for example, cryocauterization or electrocautery removal and other localized surgical procedures.

In conclusion, the hands-on experiment proves that the invention can be advantageously used as an adjunctive treatment for the treatment of premalignant lesions, particularly those caused by aggressive agents, such as viruses in the outer lining epithelium, associated with other procedures already in place. existing in the state of the art such as surgical procedures;

 UTERINE PRECANEROUS INJURIES AND EVOLUTION FOR CANCER- ASSOCIATED FACTORS-TECHNICAL STATE TREATMENTS

The so-called uterine cervical dysplasia is considered a premalignant or precancerous transformation or modification of cells of the cervix or cervix epithelium. For example purposes it is cited: Kumar, Vinay; Abbas, Abul; Faust, Nelson; & Mitchell, Richard N. (2007). Robbins Basic Pathology ((8th ed.) Ed.). Saunders Elsevier. Pp. 718-721.

In some cases cervical dysplasia remains stable or is eliminated or reversed by the immune system. If left untreated in time, however, it can become a chronic condition and develop into cervical cancer.

 Uterine cervical dysplasia is routinely diagnosed in clinical practice through the so-called Pap smear, which is used for early detection of lesions. The so-called Pap smear is a routine gynecological examination made with material in the cervical region that allows the cervical (cervical) cells to be evaluated microscopically. Shows signs related to infections in the region as well as malignant lesions.

 In addition to its classic use for tissue evaluation in the cervical region, it is also used to evaluate the effect of treatments.

 The test result is that Pap smears are grouped into five (5) categories: Class I means no abnormal cells, Class II generally indicates inflammation or infection, and Class III indicates presence of altered cells (dysplasia.).

Class III can be subdivided into three subclasses or types of dysplasia: mild, moderate or severe. In mild and moderate types it is usually indicated for cauterization. In severe dysplasia it may be necessary to remove a segment of the neck called conization or other surgical measures.

 Class IV represents a highly suspicious result for malignancy and Class V is considered representative of manifested neoplasia.

 DETERMINING CAUSES FOR CERVICAL DYSPLASIA- CHRONIC HPV INFECTION

 It is well established in the art that the determining cause for most chronic cervical dysplasias of the uterine region is infection by the so-called sexually transmitted human papilloma virus (HPV).

 There are about 100 types of HPV identified, of which about a dozen are implicated in the process that generates cervical dysplasia and its progression to cervical cancer.

 HPV-16 and HPV-18 are considered responsible for 60% of cervical cancer cases worldwide. (Munoz N, Castellsague X, by Gonzalez AB, Gissmann L. Chapter 1: HPV in the etiology of human cancer. Vaccine. 2006; 24 Suppl 3: S1-S10.)

 HPV 6, HPV-11, HPV-16, HPV-18, HPV-33, and HPV-45 are considered at high risk for carcinogenesis. An example of the early state of the art is exemplified by: Schiffman, M.H., 1992. Recent progress in defining the epidemiology of human papillomavirus infection and cervical neoplasia. Journal of the National Cancer Institute. 84 (6): 394-398.

 These cited types (HPV 6, HPV-11, HPV-16, HPV-18, HPV-33, HPV-45) and recognized as high risk are all associated with the development of cervical dysplasias, ie, cellular lesions considered precancerous as they may progress to cancer. The presence and characterization of these viral types are evaluated after the finding of cervical dysplasia, through several laboratory techniques (in situ hybridization, hybrid capture, PCR).

It is not known so far in the state of the art whether cellular modifications called dysplasias (cervical dysplasia) may be associated directly with viral activity (direct cytopathogenic effect) or indirectly due to the transformations pathogen-host interaction (indirect cytopathogenic effect) or a combination of these situations or causes.

 However, regardless of the causal factors of cervical dysplasia, it is immediately noticeable to any person skilled in the art, without further consideration or clarification, that concomitant treatment of the primary carcinogenic cause, ie, chronic viral infection previously performed in combination or subsequent to the treatment or removal of dysplasia, which is a lesion usually associated with the presence of HPV, is an important condition for therapeutic success by decreasing the chances of recurrence of the infection which may lead to dysplasia again.

 Ideally for a hypothetical treatment for the precancerous cell condition or modification, ie cervical dysplasia, which is associated with chronic HPV infection, is that this treatment can either attack or remove the altered cells or regress the presentation. to less aggressive categories on the Pap smear scale and at the same time contribute to the control of the initial causative agent, ie HPV. As will be shown herein, the invention allows effective means for such.

CERVICAL DYSPLASIA - PREVENTIVE THERAPIES - CAUSAL AGENTS (HPV) TREATMENT OPTIONS

Since chronic HPV infection has been shown to be associated with the induction of dysplasia and the evolution of this condition to cancer, several treatments have been developed and are available in the state of the art to attempt to control and / or eliminate viruses and / or at least associated lesions. Try one to perform a palliative treatment of dysplasias and cancer. For prior art examples: Jung WW, et al. Strategies against human papillomavirus infection and cervical cancer. J Microbiol. 2004 Dec; 42 (4): 255-66 and still; Scheinfeld N, Lehman DS. An evidence-based review of medical and surgical treatments of genital warts. Dermatol Online J. 2006 Mar 30; 12 (3): 5.

HPV infection occurs in three main forms of presentation; clinical, subclinical and latent: The clinical form, with the presence of macroscopic lesions (genital warts) in the anogenital region; the subclinical form, characterized by the presence of diffuse areas of dysplasia and epithelial hyperplasia, observed through the colposcope and after application of contrast (acetic acid) and latent form, ie without histological changes, but with the presence of viral DNA detected through techniques such as hybridization, hybrid capture or PCR meaning polymerase chain reaction or polymerase chain reaction ..

Traditional treatments mainly for the removal of lesions associated with HPV or its clinical manifestations, such as genital warts, involve localized treatments, with the use of caustic agents such as podophyllin and its derivatives, as well as trichloroacetic acid.

Several surgical techniques are used with varying degrees of success in the art are: local excision, cryotherapy, laser vaporization using C0 ₂ and electro cauterization. However, treatment for clinical and subclinical forms of HPV is considered inefficient and has a high degree of recurrence. They involve long periods of time and are often painful and / or disfiguring.

 PROBLEMS INVOLVING SURGICAL THERAPIES FOR DISASTER REMOVAL

 Surgical alternatives for removing HPV-infected tissues can be painful and impractical for treating extensive lesions. In the prior art, there is great controversy as to whether frequent localized posttreatment recurrences are due to reactivation of subclinical infection or originating from normal epithelium that has been left untreated. For examples of the prior art, cite: Krebs, H.-B., 1989. Management strategies. Clinical Obstetrics and Gynecology. 32 (1): 200-213.

The most common complications include pain, local discharge, ulceration, infection and long healing. Permanent scars can also happen. Results are conflicting in terms of recurrence and persistence of subclinical lesions. For examples of the prior art, cite: Ling, M.R., 1992b. Therapy of genital human papillomavirus infections. Part II: Methods of treatment. International Journal of Dermatology. 31 (11): 769-776.

 Recent advances in the state of immunotherapy

In the state of the art, the use of immunotherapy for the treatment of HPV infection and its cellular lesions (dysplasias) began with the application of BCG vaccine, originally used for the prophylactic treatment of tuberculosis and exogenous interferons (Ex: Interferon-alpha, interferon-beta, interferon-gamma) applied locally or intralesionally for increased immunity, with conflicting results. Examples of this state of the art include: Kraus, SJ & Stone, KM, 1990, Management of genital infection caused by human papillomavirus - Reviews of Infectious Diseases. 12 (suppl. 6): S620-S632.

With the development of new compounds, immunotherapy is gaining increasing space as a therapeutic option in the state of the art for treatment of HPV infections, citing the new compounds available in the state of the art:

Imiquimod: (IUPAC: - (2-methylpropyl) - 3,5,8-triazatricyclo [7.4.0.02,6] trideca-1 (9), 2 (6), 4, 7, 10,12-hexaen-7- amine, Molecular Formula: Ci ₄ Hi ₆ N _4, CAS (99011-02-6) ATC (D06BB10) PubChem (57469) DrugBank (APRD01030) is a biological response modifier, recently available in the art and topically used .

 It is approved for topical treatment of genital lesions in women caused by HPV and for the treatment of precancerous skin lesions in both sexes, such as actinic keratosis and epithelial cancer such as superficial squamous cell carcinoma and malignant melanoma in its stage. initial

 Imiquimod is known to be able to function locally as a ligand (agonist) for cell membrane receptors recognizing pathogen molecular patterns (Toll like receptor s or TLR), and is capable of activating the so-called TLR 7 and 8 which are also associated. virus recognition by cells expressing these receptors.

 Agonist (stimulating) molecules for toll-like cell receptors (TLRs) function as modifiers of the biological response because they are capable of activating the effector mechanisms of specialized cells of the immune system that contain these specific receptors in your cell wall, such as cells. dendritic.

Although the mechanism of action in imiquimod cancer and similar molecules is hypothetical because they are not completely elucidated, the use of the compound in neoplasia, supported by several authors, also stimulates the local production of cytokines associated with the TH-1 type immune response. instead activate immune system defense cells such as macrophages and NK cells, considered critical to the body's defense against intracellular pathogens and cancer. For example in the prior art, Miller, RL, et al. Imiquimod applied topically: a novel immune response modifier and a new class of drug. Int J Immunopharmacol. 1999 Jan; 21 (1): 1-14.

 Very recent studies also suggest a dual mechanism of action for imiquimod and resiquimod, that is, acting as agonist molecules (stimulants) for Toll-like cell receptors (TLRs) which would enable them as modifiers of biological response and also acting. in the so-called opioid growth factor (OGFr), which would explain its antitumor effect, regardless of the effect on the immune system. For an example of the state of the art, Ian S.Zagon et. Al, Imiquimod Upregulates the Opioid Growth Factor Receptor to Inhibit Celi Proliferation Independent of Immune Function, Experimental Biology and Medicine 233: 968-979 (2008).

 Imiquimod is reported in a clinical study of 169 patients as a preventive treatment for cutaneous carcinoma with a significant protection rate against tumor recurrence within 2 (two) years of therapy. Quirk C, Gebauer K, Owens M, Stampone P., Two-year interim results from a 5-year study evaluating clinical recurrence of superficial basal cell carcinoma after treatment with imiquimod 5% cream daily for 6 weeks.Australas J Dermatol. 2006 Nov; 47 (4): 258-65.

 The most frequent complication of using imiquimod is localized skin reactions ranging from moderate to severe. Headache, bone pain and intestinal problems associated with the use of the product are also reported. For the state of the art, exemplarily cites: Francesco Lacarrubba, et al. Advances in the use of topical imiquimod to treat dermatologic disorders, Ther Clin Risk Manag. 2008 February; 4 (1): 87-97.

Resiquimod - IUPAC (1- [4-amino-2- (ethoxymethyl) imidazo [4,5-c] quinolin-1-yl] -2-methylpropan-2-ol) Molecular Formula: C17H22N4Q2 CAS (144875-48- 9), PubChem (59603).

The compound called resiquimod is indicated for use as a biological response modifier and for its ability to bind to so-called toll-like receptors, as well as as adjuvant to therapeutic vaccines, ie to induce or assist an increase in TH-type response. 1, enhancing the effect of these therapeutic vaccines. Examples of the prior art include: Mark A Tomai et.al, Resiquimod and other immune response modifiers as vaccine adjuvants, Expert Review of Vaccines, October 2007, Vol. 6, No. 5, Pages 835-847, DOI 10.1586 / 14760584.6.5.835.

 ADVANCES IN THE STATE OF HPV PROPHYLATIC AND THERAPEUTIC VACCINE TECHNIQUES

The latest advance in the state of the art is the development of HPV vaccines, which act preventively on the major types considered carcinogenic (HPV-6, HPV-11, HPV-16, and HPV-18). They are considered effective only for women still outside their sexual maturity or without any previous HPV infection. There is no therapeutic HPV vaccine yet to ensure its elimination for patients already infected or with a history of previous infection.

 Preventive vaccines against the most prevalent viral types, ie, bivalent HPV 16/18 and tetravalent HPV 6/1 1/16/18 types, are available in the art. However, existing vaccines when used for therapeutic purposes in patients already with HPV infection have shown modest results, although with some degree of effect on cervical dysplasias.

 In the prior art, the bivalent anti-HPV vaccine (HPV-16/18 AS04-adjuvant vaccine) is reported in a study involving young women, as well as having a prophylactic or preventive effect for cervical cancer, in addition to antiviral action against HPV. , since it significantly decreased the number of cervical lesions (cervical dysplasia) considered precancerous lesions of patients participating in the clinical trial.

 For example prior art: J Paavonen, P Naud, J Salmeron, CM Wheeler, S-N Chow, D Apter, H Kitchener, X Castellsague, J Teixeira, SR Skinner, J Hedrick, U Jaisamrarn, G Limson, S Garland , A Szarewski, B Romanowski, FY Aoki, TF Schwarz, WAJ Poppe, Bosch FX, D Jenkins, K Hardt, T Zahaf, D Descamps, F Struyf, M Lehtinen, G Dubin - Efficacy of human papillomavirus (HPV) -16 / 18 AS04- adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICE): final analysis of a double-blind, randomized study in young women ", The Lancet, Volume 374, Issue 9686, Pages 301 - 314, 25 July 2009., DOI: 101016 / 0140-6736 (09) 61248-4.

Therapeutic HPV vaccination using a quadrivalent vaccine (anti HPV 6/1 1 / 16/18 vaccine) is also reported to be effective as prophylactic or preventive therapy in the treatment of precancerous lesions in the vaginal region. For example of prior art: Efficacy of a Quadrivalent Prophylactic Human Papillomavirus (Types 6, 1 1, 16, and 18) LI Virus-Like-Particle Vaccine Against High-Grade Vulval and Vaginal Lesions: A Combined Analysis of Three Randomized Clinical Trials, "- The Lancet (2007; 369 (9574): 1693-1702).

TREATMENT OF PRECANEROUS INJURIES AND CERVICAL DYSPLASIAS - STATE OF THE TECHNIQUE

 It is generally accepted that the first stage in the development of cervical cancer is the condition known as dysplasia, which occurs when squamous cells in the cervical region become abnormal in size and shape and begin to multiply.

 Cervical dysplasia (Pap smear grade III) is classified as mild, moderate or severe, depending on the degree of cellular abnormality on microscopic examination.

In so-called mild dysplasia, abnormal cells occupy only the superficial layer of the epithelium. This condition may progress if left untreated in time, progressing to severe dysplasia.

 The severe dysplasia phase, if left untreated, will in most cases progress to the maximum stage or degree, which is early cervical cancer, also called Carcinoma in situ or Tumor in situ.

 For destruction and / or removal of cervical epithelial lesions, which are usually associated with the action of the human papilloma virus (HPV), chemical abrasion is used with caustic products such as podophylline and surgical procedures performed by mechanical, electrical means. (cauterization) and freezing (cryosurgery).

In the prior art, the anti-HPV vaccine (HPV-16/18 AS04-adjuvant vaccine) is reported in a study involving young women, as also having a prophylactic or preventive effect for cervical cancer, as having significantly decreased the number of lesions. cervical dysplasia (cervical dysplasia) considered precancerous lesions of patients participating in the clinical trial.

For example prior art: J Paavonen, P Naud, J Salmeron, CM Wheeler, S-N Chow, D Apter, H Kitchener, X Castell sague, JC Teixeira, SR Skinner, J Hedrick, U Jaisamrarn, G Limson, S Garland, A Szarewski, B Romanowski, FY Aoki, TF Schwarz, WAJ Poppe, FX Bosch, D Jenkins, K Hardt, T Zahaf, D Descamps, F Struyf, M Lehtinen, G Dubin - Efficacy of human papillomavirus (HPV) - 16 / 18 AS04- adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICITY): final analysis of a double-blind, randomized study in young women ", The Lancet, Volume 374, Issue 9686, Pages 301 - 314, 25 July 2009., DOI: 10.1016 / S0140-6736 (09) 61248 -4.

 Therapeutic HPV vaccination using quadrivalent vaccine (anti-HPV-6/1/1 1/16/18 vaccine is also reported to have some efficacy as prophylactic or preventive therapy in the treatment of precancerous lesions in the vaginal region. of the state of the art: Efficacy of a Quadrivalent Prophylactic Human Papillomavirus (Types 6, 1 1, 16, and 18) LI Virus-Like-Particle Vaccine Against High-Grade Vulval and Vaginal Lesions: A Combined Analysis of Three Randomized Clinical Trials, " - The Lancet (2007; 369 (9574): 1693-1702)

 Regardless of the techniques used to remove damaged or altered tissue, it is simple for any person skilled in the art to understand that the success of preventive, curative or palliative treatments of precancerous cervical lesions, ie cervical dysplasias of any nature by preventing progression to cancer, it is also influenced by effective treatment for the most important causative agent, namely HPV, mainly of the types identified as carcinogenic (HPV 6/1 1/16/18).

 TREATMENT OF PRECERIOUS INJURIES AND CERVICAL DYSPLASIAS- EXISTING PROBLEMS-TECHNICAL STATE

In the state of the art, the relapse rate for all existing excisional or surgical treatments for removal / treatment of precancerous cervical lesions or changes (dysplasias) is very high, precisely because of the extreme difficulty in removing the main causative agent, ie , the human papilloma virus or HPV.

The so-called preventive vaccines (bivalent anti-HPV 16/18 and tetravalent HPV-6/1 1/16/18) are effective only for non-carriers and have reduced effect when treatments for patients with chronic dysplasia, post-infection are used. HPV as already cited herein.

Therefore, the importance of the immunotherapeutic approach should be considered to provide viable solutions to the problem, as there are state-of-the-art immunotherapy-based solutions for HPV treatment, such as preventive anti-HPV vaccines and further modifying compounds. biological response such as imiquinod and resiquimod. In view of this set of facts and the recognized immunomodulatory properties of the biological response modifier (ammonium phospholinoleate palmitoleate anhydride protein aggregate) the invention as shown below is especially suitable and has been tested for localized treatment (topical). ) also for the treatment of cervical dysplasia associated with the human papilloma virus, used in a novel and novel form of use for the compound, namely topical intrauterine application.

 To demonstrate in practice the efficacy of the present invention in the treatment of HPV-associated cervical dysplasia a practical example of its use in a clinical trial will be provided in patients with chronic HPV uterine infection and infection-associated cervical dysplasias ranging from mild to moderate, who did not respond satisfactorily to one of the standard and most commonly used treatments in the state of the art, namely: electro-cauterization surgery.

 This practical example is given for explanatory purposes only and is not intended to diminish or limit the scope or scope of the invention.

 EXAMPLE OF PRACTICAL USE NUMBER - USE OF THE INVENTION FOR THE TOPICAL TREATMENT OF VIRUS-ASSOCIATED UTERINE INJURIES - TABLE 8A AND TABLE 8B

To demonstrate in practice the efficacy of the present invention in the topical treatment of HPV-associated cervical dysplasia, a practical example of its use in a clinical trial will be provided in patients with chronic and recurrent HPV infection and cervical dysplasias associated with mild to moderate infection. severe patients who did not respond satisfactorily to one of the standard and most commonly used treatments in the state of the art, namely: electrocautery surgery.

 This practical example is given for explanatory purposes only and is not intended to diminish or limit the scope or scope of the invention.

Clinical Study: Application of the biological response modifier (ammonium and magnesium phospholinoleate-palmitoleate anhydride protein aggregate) post-surgery in 25 women with moderate to severe dysplasia confirmed by laboratory findings (Pap smear) and positive serology (PCR) for HPV. All patients had a previous history of routine surgical procedures to remove damaged tissue (electro-cauterization) in the months prior to the clinical trial, with recurrence of dysplasia and infection in all cases.

 The patients were previously submitted to the clinical trial to routine exams to evaluate the degree of dysplasia (Pap smear) and material from the cervical region was also collected for research and typing for human papilloma virus (HPV).

 Of the 25 participating patients, 15 were classified as having HPV-associated moderate cervical dysplasia 1 1, 5 with HPV-18-associated moderate cervical dysplasia, and 5 with HPV-16 and HPV-18 severe cervical dysplasia. at admission are shown in Table 8-A

 (*) Virus detection and typing method: PCR - Amplicor Kit (HPV) - Roche

 (**) Method of detection and classification of cervical dysplasia: Pap smear

Periodicity: Collection of cervical material for research and classification for dysplasia and HPV was performed before (baseline) and 6 months after the end of the clinical trial.

 Sample characterization: Patients who were previously surgically treated by electro cauterization and presented signs of recurrent cervical dysplasia, classified by Pap smear as dysplasias ranging from medium to severe upon admission to the clinical trial (Table 8-A).

Viral typing: All patients (100%) at admission had at least one viral type considered at high risk for developing malignancy, and five (5) of the patients had an association of more than one viral type (HPV 16 and HPV 18) (Table 8a) Clinical Trial Design: All patients underwent the same previous surgical procedure, ie, electro cauterization to remove altered tissue (dysplasia).

 They also received the topically applied biological response modifier being specially formulated for this purpose as an appropriate vaginal cream (pH 7.0) with a concentration of the active ingredient (ammonium and magnesium phospholineate palmitoleate anhydride protein aggregate) of 20% applied daily using intrauterine applicator for 2 weeks, starting the first dose 1 day after surgery with electro cauterization.

 Follow-up: All patients were followed monthly through clinical examinations and colposcopy.

 Final evaluation: The patients were evaluated again 180 days after the end of the surgical procedure combined with the application of the topical biological response modifier (cream) to classify dysplasia and eventual presence of HPV virus.

 Results: The results are presented in Table 8-B and commented below.

 (*) Virus detection and typing method: PCR - Amplicor Kit (HPV) - Roche

 (**) Method of detection and classification of cervical dysplasia: Pap smear

TABLE 8-B - DISCUSSION OF RESULTS

The use of the present invention, ie the biological response modifier (ammonium phospholinoleate palmitoleate anhydride protein aggregate) applied topically associated with a surgical procedure (electro cauterization) yielded surprising and remarkable results in the patients participating in the study. clinical trial, both for action on cervical dysplasia and for effect on causative agent (HPV). Although the sample is limited in number, it should be noted that all patients had previously undergone the same surgical procedures for removal of modified tissue (cervical dysplasia) and relapsed, ie, had 100% relapses.

The recurrence rate with the use of the invention, ie, biological response modifier associated with surgery (electro cauterization) was 0% (zero percentage), ie none of the twenty patients showed signs of dysplasia again, when evaluated 180. days after the end of the clinical trial, although 5 (five) of them still had HPV on the assessment date after the end of the clinical trial, ie, 180 days after.

 Comparatively, the previous relapse rate at the beginning of the experiment, reported for these same patients, when treated only by surgical methods, was 100% relapse for cervical dysplasia and viral presence.

 It is noteworthy that these patients no longer had cervical dysplasia during the evaluation period (180 days after the end of the clinical trial), which clearly indicates a direct effect of the invention on cell alteration (cervical dysplasia), ie, in cells with lesion considered potentially precancerous, regardless of the presence of the virus, since laboratory testing in these patients indicates remnant HPV in 5 (five) patients.

This effect of the invention on precancerous lesion (cellular dysplasia) regardless of the presence of the virus can be stated, since for all patients, on admission to the clinical trial the classification of dysplasia ranged from moderate to severe and after treatment with the invention to dysplasia was completely eliminated despite the presence of viruses in a small percentage, that is, only for 5 (five) of the patients (Table 8-B). ABSOLUTE NEWS OF THE INVENTION FOR TOPICAL TREATMENT OF HPV PRECERNANT INJURIES.

PI 0801803-0 and WO / 2009/097670 describe the use of the biological response modifier (ammonium phospholinoleate palmitoleate anhydride protein aggregate) as a component of drug combinations or combinations against optional or strict intracellular pathogens or parasites and This also encompasses general action against viruses as they are classified as strict intracellular parasites. However, it can be stated that this prior invention (PI 0801803-0, WO / 2009/097670), ie practical application of the biological response modifier (ammonium phospholinoleate palmitoleate anhydride protein aggregate) for treatment of infections caused by intracellular parasites is totally distinct from the present invention, including in the particular case involving the treatment of pre-cancerous associated lesions or cervical dysplasias virus (HPV) action.

The previous invention (PI 0801803-0, WO / 2009/097670) relates to the use of the systemic biological response response modifier (ammonium phospholinoleate palmitoleate anhydride protein aggregate) for the curative treatment of diseases. infectious diseases, including those caused by viruses.

 Finally, WO / 2011/082458 describes the use of protein ammonium phospholinoleate anhydride in the adjuvant treatment of cervical dysplasia and HPV virus infection, but such practical application also refers to the use of the compound of the present invention systemically.

This means that in a prior application, that is, in WO / 2011/082458 the utility or practical effect of the invention described therein depends upon the obligatory use of the injectable route for the compound to produce the desired effects.

The present invention is intended for a totally different use or purpose, namely the practical use of the biological response modifier (ammonium phospholinoleate palmitoleate anhydride protein aggregate) alone or in combination with other non-medicated and / or other treatments. also for the treatment of cancer, but in topical form, that is, applied directly to the injured tissue, which differs radically from previous requests.

 Finally, it is still readily understood by any person skilled in the art that the use of the topical route of use when dealing with similar drugs has some advantages compared to the use of the systemic route of action, which depends to exert its effect of use, using more aggressive methods of introducing the compound into the body, such as subcutaneous and / or intramuscular injections, for example.

Among the comparative advantages that can be cited for the use of topically applied drugs over injectables, in the case of similar compounds, are a lower rate or possibility of local reaction effects, such as muscle pain and / or inflammation, and less discomfort for users who use the topical pharmaceutical form, which leads to greater adherence of patients to treatment protocols.

 In the case of similar drugs, another comparative advantage that the use of the topical route allows is the use of much larger amounts or concentrations of the active ingredient at the site of injury compared to the amounts or concentrations made possible by the use of the same compounds. injected into the body.

 Finally the possibility of chemical and / or structural changes in the drug due to the organism metabolism is smaller when using the topical route of application. COMPARATIVE ADVANTAGES OF THE USE OF THE INVENTION AS A TYPICAL ADJUVENT TREATMENT AGAINST PREMALIGNAL AND MALIGNAL INJURIES OF THE COATING EPITHELIUM.

 Taking into account the information contained in this report and still examples of practical use, it can be stated that compared to drugs used in the treatment of cancer affecting the external and internal epithelial lining, notably in the treatment of urinary bladder cancer, HPV-associated malignant skin and uterus lesions being used alone and / or in combination with other drugs used in the state of the art, the use of the invention provides significant advances in the state of the art.

Some of the advantages and advances taking into account the state of the art include:

 A - It has even been shown by practical examples that the use of the compound of the present invention (ammonium phospholinoleate palmitoleate anhydride protein aggregate) is superior in therapeutic outcome to the best existing immunotherapeutic drug for the treatment of urinary bladder cancer, which is the BCG vaccine (Table 4).

B - It has even been shown with practical examples that the compound (ammonium phospholinoleate palmitoleate anhydride protein aggregate) used alone and topically applied is superior in therapeutic outcome to the major chemotherapeutic agents used in the state. of the technique for the treatment of malignant lesions of the inner lining epithelium, notably in the urinary bladder (Table-5). C - The use of the invention represented by the isolated use of the compound (ammonium phospholinoleate palmitoleate anhydride protein aggregate) in the treatment of urinary bladder cancer has not been accompanied by toxicity indicative side effects such as hematuria. (Table 4).

D) It has even been shown by practical examples that the use of the invention in conjunction with chemotherapeutic and immunotherapeutic agents not only potentiates the effects of the compounds on the treatment of malignant lesions located in the lining epithelium, notably the urinary bladder internal epithelium. , as it still contributes significantly to the reduction of unwanted side effects of such treatments (Table - 6).

 E) It has even been shown by practical examples that the use of the invention makes it possible to visualize that the compound of the invention (ammonium phospholinoleate palmitoleate anhydride protein aggregate) can replace the aforementioned treatments, in this case Mitomycin C and BCG vaccine if therapeutic effect fails or toxicity impedes continued use. (Table -6)

F) It has even been shown with practical examples that the compound (ammonium phospholineate palmitoleate anhydride protein aggregate) used after surgical or excisional lesion procedure is effective for topical adjuvant treatment of premalignant epithelial lesions external and internal lining associated with the action of aggressive agents such as HPV virus notably on the skin and uterine region (Tables 7 and Table 8-a and Table 8-B)

 EXTRAPOLATION OF USE OF THE INVENTION FOR TUMORS LOCATED IN OTHER LUMEN DONATED ORGANS USING APPLICATION DEVICES

These surprising effects of the use of the compound (ammonium and magnesium phospholinoleate palmitoleate anhydride protein aggregate) in the treatment of cancer through local contact in the affected epithelium, exemplified by the experiments cited herein, ie local treatment of precancerous lesions HPV virus associated external epithelium (skin) enable the invention for topical or localized treatment of malignant and premalignant lesions located on the outer lining epithelium.

Equally surprising are the effects of using the compound (phospholinoleate-ammonium magnesium palmitoleate anhydride protein aggregate) in the treatment of cancer through local contact in the affected internal epithelium, exemplified by the experiments. cited herein, ie topical (intravesical) treatment of urinary bladder cancer and HPV-associated uterine lesions proves the ability of the invention for topical or localized treatment of malignant and premalignant lesions located in the lining epithelium notably urinary bladder and uterus. These surprising effects of using the compound (ammonium and magnesium phospholinoleate palmitoleate anhydride protein aggregate) in the treatment of cancer through local contact on the affected epithelium, exemplified by the experiments cited herein, ie local (intravesical) cancer treatment Urinary bladder designs enable or indicate the invention for the treatment of cancer by affecting internal anatomical regions by simply being able to be reached or achieved by local drug delivery devices such as catheters, stents and other instruments.

In addition to mechanical devices such as catheters and others, other means of transporting and releasing drugs locally, for example capsules and dragees for the controlled release of medicaments containing the compound of the invention can be used so that they can be reached and contact the epithelium of anatomical regions of interest such as stomach and intestine.

 For the treatment of lesions on the outer lining epithelium, all types and types of pharmaceutical carriers known in the art, such as creams, lotions and other drug delivery and dispersion carriers may be used for local or topical application purposes. of the invention.

 In summary, all types of mechanical or pharmacological devices capable of transporting and releasing medicaments may be used to provide the compound of the invention for the treatment of lesions in the outer lining epithelium and for the treatment of lesions in the inner lining epithelium. organs with cavities such as the mouth, esophagus, stomach, small intestine, urethra and urinary bladder, uterus.

 PHARMACEUTICAL FORMULATIONS OR FORMS FOR PRACTICAL USE OF THE INVENTION

For purely explanatory purposes, the following are two pharmaceutical formulations developed for practical use of the invention which have already been found to be viable for localized or topical use of the invention in animal and human models and which have been presented in this report. The first formulation essentially comprises suspending the compound of the invention in saline (0.9% NaCl) for its use or deposition within cavitated organs for the treatment of premalignant or malignant lesions of the lining epithelium using catheters. or other devices.

This formulation has the advantage that it can be applied to any inner lining epithelium because the 0.9% saline solution is known to be harmless to cellular components.

 The second formulation, also already used in practice, is mentioned in this report and essentially comprises the formulation of the ammonium phospholinoleate palmitoleate anhydride protein aggregate with the active compound concentration ranging from 15% to 30-% . in cream form what occurs when the compound is added and homogenized to an inert base or excipient formed of sterile petroleum jelly and sterile deionized distilled water using a mixer. The resulting final pH is around 7.

ADDITIONAL INFORMATION ABOUT FUTURE USES FOR INVENTION ISOLATED OR ASSOCIATED WITH OTHER DRUGS AND THERAPIES

 For the purposes of the present invention, the immunomodulator (ammonium phospholinoleate palmitoleate anhydride protein aggregate) may be used alone for topical application and may also be used for topical application with other therapeutic modalities in combination or in combination. of treatments.

 The other other active substances to be optionally used when using the invention in combination or combination with compounds may vary in species, type, quality and quantity according to the specific needs of the disease.

The other active substances, which act against various types of malignant and premalignant lesions and even causal agents, such as HPV viruses, are cited here only as specific examples of the various product classes in the current state of the art, such as antineoplastic, chemotherapeutic and immunotherapeutic, in a non-exhaustive classification or enumeration. Nothing precludes other topical cancer substances and therapies not expressly mentioned herein as being part of the state of the art or yet to be discovered and made available, used or likely to be used. proposed for use for the purposes of the present invention as long as the immunomodulator (ammonium phospholinoleate palmitoleate anhydride protein aggregate) continues to be used or maintained in combination or combination to continue to produce the desired effects.

COMPOUND USED FOR PURPOSE OF THIS INVENTION

The present invention utilizes a biological response modifier or immunomodulatory compound which is known in the art and termed as a protein aggregate of ammonium phospholinoleate palmitoleate anhydride and is originally reported in PI - 0305373-3 US 2006/0093628 A1, EP 1529784 A1, but is used in a manner totally different from the previous existing product applications described in the prior art.

 This compound now used for topical application for the purposes of the present invention is characterized in that it comprises essentially a magnesium ammonium phospholinoleate palmitoleate anhydride protein aggregate of molecular weight 320,000 Dalton (320 KDa) and has been previously described in PI - 0305373 -3 US 2006/0093628 Al, EP 1529784 Al.

 This compound used in the present invention, in the chemical analysis showed the presence of 11.6 ± 4.0% total lipids, being 22.7 ± 5.0% palmitoleic acid, 42.9 ± 2.0% acid. 32.0 + 3.0% oxidized linoleic acid, 20.1 ± 0.9% Mg ions, 10.0 ± 3.3% ammonium ions, 45.2 ± 2.7% phosphate and 0.49 ± 0.01% protein, as per PI - 0305373-3 US 2006/0093628 Al, EP 1529784 Al.

 The protein is distributed in percent as follows; Asp 7.19%; Thr 3.56%; Ser 7.56%; Glu 8.53%; Pro 0.5%; Gly 9.69%; Ala 7.46%; Val 1.0%; Met 4.38%, Isolate 2.54%, Leu 3.03%, Tyr 0.5%, Phe 1.0%, His 2.83%; Lys 3.56%, Trp 1.3% and Arg 35.2%, as per PI - 0305373-3 US 2006/0093628 Al, EP 1529784 Al.

The method of production of the immunomodulator (ammonium phospholinoleate palmitoleate anhydride protein aggregate) used for the purposes of the present invention is also contained and reported in the prior art in PI - 0305373-3 US 2006/0093628 Al, EP 1529784 A1, comprising essentially the use of the fungus Aspergillus oryzae (A.oryzae) in appropriate culture medium, resulting ultimately in obtaining the immunomodulatory compound that was specifically selected for use for the purposes of the present invention. For further information regarding obtaining the compound used in the present invention, mode of use, biological properties and other information of interest, see PI - 0305373-3 US 2006/0093628 Al, EP 1529784 Al. Without the need for further information, it can be stated that anyone skilled in the art, with the aid of only the information and explanations contained herein, is able to understand and use the invention to its fullest extent.

Although the invention is intended for the treatment of humans, nothing prevents other species of animals from being subjected to their use and benefiting from their therapeutic characteristics and qualities.

Claims

1 - "IMMUNOMODULATING COMPOUND FOR TREATMENT OF CANCER TUMORS LOCATED IN THE INTERNAL AND EXTERNAL EPITELIAL TISSUE" used in the form of the present invention for topical adjuvant treatment of cancer and precancerous lesions situated in the internal and external epithelial tract, and especially in the treatment of urinary, uterine and skin bladder used alone or used in combination with or in combination with other drug treatments such as chemotherapy and / or immunotherapy and / or non-drugs such as surgery.

 2 - "IMMUNOMODULATING COMPOUND FOR TREATMENT OF CANCER TUMORS LOCATED IN THE INTERNAL AND EXTERNAL EPITELIAL TISSUE" according to claim 1, characterized in that said treatments are performed with the biological response modifier (ammonium and magnesium phospholinoleate palmitoleate anhydride protein aggregate). ) which is defined in the state of the art as a protein aggregate of ammonium phospholinoleate palmitoleate anhydride with a molecular weight of 320,000 Dalton (320 kDa) which in the chemical analysis showed the presence of 1 1,6 ± 4,0 % of total lipids, being 22.7 ± 5.0% palmitoleic acid, 42.9 ± 2.0% linoleic acid and 32.0 ± 3.0% oxidized linoleic acid, 20.1 ± 0.9 % Mg ions, 10.0 ± 3.3% ammonium ions, 45.2 ± 2.7% phosphate and 0.49 ± 0.01% protein; the protein being distributed in percent as follows; Asp 7.19%; Thr 3.56%; Ser 7.56%; Glu 8.53%; Pro 0.5%; Gly 9.69%; Ala 7.46%; Val 1.0%; Met 4.38%, Isolate 2.54%, Leu 3.03%, Tyr 0.5%, Phe 1.0%, His 2.83%; Lys 3.56%, Trp 1.3% and Arg 35.2%.

3 - "IMMUNOMODULATING COMPOUND FOR TREATMENT OF CANCER TUMORS LOCATED IN THE INTERNAL AND EXTERNAL EPITELIAL TISSUE", ammonium and magnesium phospholineate palmitoleate protein aggregate, ie the compound of claims 1 and 2 for topical adjuvant treatment of cancer internal epithelial tissue, ie the epithelial tissue of other organs with internal light such as the mouth, esophagus, stomach, small intestine, urethra and urinary bladder, uterus and also in the outer lining epithelial tissue, ie the skin, used alone or used in combination or in combination with other drug treatments such as chemotherapy (eg Mitomycin C, Thiotepa, Adriamycin) and / or immunotherapy (eg BCG, Interferon, IL-2) and / or non-medications such as surgery.

 4 - "COMPOUND 1MUNOMODULATOR FOR TREATMENT OF CANCER TUMORS LOCATED IN THE INTERNAL AND EXTERNAL EPITELIAL TISSUE", Ammonium and Magnesium Phospholinoleate-Palmitoleate Anhydride Protein Aggregate, that is, the compound of claims 1 and 2 for topical adjuvant cancer treatment internal and external epithelial and especially for use alone or in combination with or in combination with other medicinal treatments such as chemotherapy (eg Mitomycin C, Thiotepa, Adriamycin) and / or immunotherapy (eg BCG, Interferon, IL-2) to enhance the effect of such drug treatments on a purely exemplary enumeration.

 5 - "IMMUNOMODULATING COMPOUND FOR TREATMENT OF CANCER TUMORS LOCATED IN THE INTERNAL AND EXTERNAL EPITELIAL TISSUE", ammonium and magnesium phospholineate palmitoleate protein aggregate, ie the compound of claims 1 and 2 for topical topical treatment of cancer affecting internal and external epithelial tissue and especially for use alone or in combination with or in combination with other drug treatments such as chemotherapy (eg Mitomycin C, Thiotepa, Adriamycin) and / or immunotherapy (eg BCG , Interferon, IL-2) to lessen the toxic side effects of such treatments, such as hematuria.

6 - "IMMUNOMODULATING COMPOUND FOR TREATMENT OF CANCER TUMORS LOCATED IN THE INTERNAL AND EXTERNAL EPITELIAL TISSUE", Ammonium and Magnesium Phospholinoleate-Palmitoleate Anhydride Protein Aggregate, ie Compound of Claims 1 and 2 for Adjuvant Topical Treatment of Cancer Affecting Tissue internal and external epithelial and especially for use alone or in combination with or in combination with other drug treatments such as chemotherapy (eg Mitomycin C, Thiotepa, Adriamycin) and / or immunotherapy (eg BCG, Interferon, IL-2) and especially to be used as a surrogate treatment in case of need for interruption of adjunctive BCG immunotherapeutic treatment in urinary bladder cancer. 7 - "IMMUNOMODULATING COMPOUND FOR TREATMENT OF CANCER TUMORS LOCATED IN THE INTERNAL AND EXTERNAL EPITELIAL TISSUE", Ammonium and Magnesium Phospholinoleate Palmitoleate Anhydride Protein Aggregate, ie Compound of Claims 1 and 2 for Adjuvant Topical Treatment of Cancer Affecting Tissue internal and external epithelial and especially to be used alone or used in combination or in combination with other drug treatments such as chemotherapy and / or immunotherapy and especially to be used as a substitute treatment in the event that adjuvant chemotherapy treatment is discontinued (e.g. example: Mitomycin C, Thiotepa, Adriamycin) in urinary bladder cancer.

 8 - "IMMUNOMODULATING COMPOUND FOR TREATMENT OF CANCER TUMORS LOCATED IN THE INTERNAL AND EXTERNAL EPITELIAL TISSUE", Ammonium and Magnesium Phospholinoleate Palmitoleate Anhydride Protein Aggregate, ie Compound of Claims 1 and 2 for Adjuvant Topical Treatment of Cancer Affecting Tissue internal and external epithelial and especially to be used as a palliative treatment in cancer affecting the urinary bladder and uterus in cases of contraindication or absolute impossibility of performing radical surgical procedures such as cystectomy and others.