WO2023001895A1 - Recombinant mycobacterium as an immunotherapeutic agent for the second-line therapy of bladder carcinoma - Google Patents
Recombinant mycobacterium as an immunotherapeutic agent for the second-line therapy of bladder carcinoma Download PDFInfo
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Classifications
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/04—Mycobacterium, e.g. Mycobacterium tuberculosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
- A61K2039/522—Bacterial cells; Fungal cells; Protozoal cells avirulent or attenuated
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
- A61K2039/523—Bacterial cells; Fungal cells; Protozoal cells expressing foreign proteins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
- A61K2039/585—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation wherein the target is cancer
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- A—HUMAN NECESSITIES
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/80—Vaccine for a specifically defined cancer
Definitions
- the invention relates to a recombinant Mycobacterium cell for use as an immunotherapeutic agent in the therapy of bladder carcinoma, particularly in the second-line therapy of non-muscle-invasive bladder carcinoma.
- Urothelial bladder carcinoma is the 5th most common cancer. In the United States, about 75.000 new cases are diagnosed each year 4.5% of all new cancers, and approximately 15.600 deaths are expected. In Germany, about 16.000 new cases are diagnosed each year. Because a recurrence of disease is likely in bladder carcinoma, patients must undergo surveillance for an extended period.
- bladder carcinomas begin in transitional epithelial cells that make up the inner lining of the bladder. As these tumors grow, they can invade the surrounding connective tissue and muscle. In advanced disease, tumors spread beyond the bladder to nearby lymph nodes or pelvic organs or metastasize to more distant organs such as lung, liver, and bone.
- the overall 5-year survival rate for bladder carcinoma is 77%, and this rate has not changed significantly over the last 10 years.
- the 5-year relative survival rates for patients with tumors restricted to the inner layer of the bladder are 96% and 69%, respectively.
- the rates drop to 34% for those with disease that has spread locally beyond the bladder and to 6% with distant metastases.
- Recurrence and progression to muscle-invasive disease may lead to additional chemotherapeutical, surgical, and radio-oncological interventions including cisplatin-based chemotherapy, transurethral resection of the bladder (TURB), cystectomy and chemo-radiotherapy.
- Recurrent bladder carcinoma may be treated with combination therapy regimens, including gemcitabine plus cisplatin or methotrexate, vinblastine, doxorubicin plus cisplatin.
- An alternative option for recurrent patients is a re-treatment with conventional BCG therapy (Yates et al, Eur Urol 62 (2012), 1088-1096).
- an object of the present invention to provide an improved treatment for patients failing to respond to first-line conventional BCG therapy as these patients are at high risk of cancer progression.
- An improved treatment of these high-risk patients will increase bladder preservation rates and consequently improve quality of life and decrease health costs.
- a recombinant BCG strain expressing a phagolysosomal escape domain is described in WO 99/101496, the content of which is herein incorporated by reference.
- the phagolysosomal escape domain enables the strain to escape from the phagosome of infected host cells by perforating the membrane of the phagosome.
- a urease-deficient recombinant strain was developed. This strain is disclosed in WO 2004/094469, the content of which is herein incorporated.
- WO 2012/085101 discloses that a recombinant BCG strain expressing membrane-perforating listeriolysin (Hly) of Listeria monocytogenes and devoid of urease C induces superior protection against aerogenic challenge with Mycobacterium tuberculosis ( Mtb ) as compared to parental BCG in a preclinical model. Further, it is shown that both the recombinant and the parenteral strain induce marked Th1 immune responses, whilst only the recombinant BCG strain elicits are profound Th17 response in addition.
- listeriolysin Hly
- Mtb Mycobacterium tuberculosis
- WO 2016/177717 discloses that a recombinant urease-deficient and listeriolysin-expressing recombinant BCG strain induces a superior immune response compared to the parenteral BCG in an animal model. Further, the start of a human clinical phase I/ll trial using recombinant BCG as an immunotherapeutic agent in patients after a first standard BCG therapy is reported.
- a first aspect of the present invention relates to a recombinant Mycobacterium cell, which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide comprising:
- a phagolysosomal escape domain for use in a method, wherein the recombinant Mycobacterium cell is administered as an immunotherapeutic agent to a subject, e.g., a human subject suffering from bladder carcinoma, particularly from non-muscle- invasive bladder carcinoma as a second-line therapy.
- a subject e.g., a human subject suffering from bladder carcinoma, particularly from non-muscle- invasive bladder carcinoma as a second-line therapy.
- the present invention further relates to a method for the immunotherapeutic treatment of bladder carcinoma, particularly of non- muscle-invasive bladder carcinoma in a subject, particularly in a human subject, comprising administering to said subject as a second-line therapy a recombinant Mycobacterium cell, which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide comprising:
- a further aspect of the present invention relates to a recombinant Mycobacterium cell, which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide comprising:
- a phagolysosomal escape domain for use in the immunotherapeutic treatment of bladder carcinoma wherein the recombinant Mycobacterium cell is administered to a subject suffering from bladder carcinoma, particularly from non-muscle-invasive bladder carcinoma, more particularly from recurrent bladder carcinoma as a second-line therapy.
- the present invention further relates to a method for the immunotherapeutic treatment of bladder carcinoma, particularly of non- muscle-invasive bladder carcinoma, more particularly from recurrent bladder carcinoma in a subject, particularly in a human subject, comprising administering to said subject as a second-line therapy a recombinant Mycobacterium cell, which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide comprising:
- a further aspect of the present invention is a recombinant Mycobacterium cell which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide comprising:
- a phagolysosomal escape domain for use as an immunotherapeutic agent in the treatment of bladder carcinoma, in particular recurrent bladder carcinoma, wherein the subject to be treated has relapsed and/or has progressed after a first treatment of bladder carcinoma, particularly after a first treatment with conventional BCG therapy.
- the present invention further relates to a method for the immunotherapy of bladder carcinoma in a subject in need thereof, particularly of non-muscle-invasive bladder carcinoma, more particularly from recurrent bladder carcinoma, wherein the subject has relapsed and/or has progressed after a first treatment of bladder carcinoma, particularly after a first treatment with conventional BCG therapy, comprising administering to said subject a recombinant Mycobacterium cell, which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide comprising:
- a further aspect of the present invention relates to a recombinant Mycobacterium cell, which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide comprising:
- a phagolysosomal escape domain for use in a method, wherein the recombinant Mycobacterium cell is administered as an immunotherapeutic agent to a subject suffering from bladder carcinoma, particularly from non-muscle-invasive bladder carcinoma, more particularly from recurrent bladder carcinoma, wherein disease recurrence is inhibited for a time period of at least 1 year, particularly for a time period of at least 2 years, of at least 3 years, or of at least 4 years.
- the present invention further relates to a method for the immunotherapeutic treatment of bladder carcinoma, particularly of non- muscle-invasive bladder carcinoma, more particularly from recurrent bladder carcinoma in a subject, particularly in a human subject, comprising administering to said subject a recombinant Mycobacterium cell, which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide comprising:
- a still further aspect of the present invention relates to a recombinant Mycobacterium cell, which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide comprising:
- a phagolysosomal escape domain for use in a method, wherein the recombinant Mycobacterium cell is administered as an immunotherapeutic agent to a subject suffering from bladder carcinoma, particularly from non-muscle-invasive bladder carcinoma, more particularly from recurrent bladder carcinoma wherein overall survival is increased in a time period of at least 1 year, particularly in a time period of at least 2 years, of at least 3 years, or of at least 4 years.
- the present invention further relates to a method for the immunotherapeutic treatment of bladder carcinoma, particularly of non- muscle-invasive bladder carcinoma, more particularly from recurrent bladder carcinoma in a subject, particularly in a human subject, comprising administering to said subject a recombinant Mycobacterium cell, which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide comprising:
- a phagolysosomal escape domain wherein overall survival is increased in a time period of at least 1 year, particularly in a time period of at least 2 years, of at least 3 years, or of at least 4 years.
- a still further aspect of the present invention relates to a recombinant Mycobacterium cell, which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide comprising:
- a phagolysosomal escape domain for use in a method for improving the life quality of a subject suffering from bladder carcinoma, particularly from non-muscle-invasive bladder carcinoma, more particularly from recurrent bladder carcinoma, wherein the recombinant Mycobacterium cell is administered as an immunotherapeutic agent thereby reducing or avoiding cystectomy in said subject.
- the present invention further relates to a method for improving the life quality of a subject suffering from bladder carcinoma, particularly from non- muscle-invasive bladder carcinoma, more particularly from recurrent bladder carcinoma in a subject, particularly in a human subject, comprising administering to said subject a recombinant Mycobacterium cell, which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide comprising:
- the present invention relates to a second-line therapy with rBCG in combination with at least one of:
- the present invention relates to an improvement of life quality comprising reducing or the need of cystectomy in combination with at least one of:
- the present invention relates to a second-line therapy in combination with:
- second-line immunotherapy refers to the treatment of a subject, particularly a human subject, after failure of a first-line therapy.
- first-line therapy particularly means disease recurrence and/or disease progression including progression of the primary tumor and/or formation of metastases after first-line therapy. More particularly, the term “failure” means disease recurrence.
- first-line therapy particularly refers to a first-line therapy including an immunotherapy, and more particularly to a first-line immunotherapy comprising administration of standard BCG without a phagolysosomal escape domain as described herein, such as previously approved standard BCG as described in Rentsch, C A, Eur Urol 2014, PMID: 24674149.
- second-line immunotherapy comprises administration of a recombinant Mycobacterium cell as described herein after a single “first-line therapy” cycle or after multiple, e.g., 2, 3 or more “first-line therapy” cycles, particularly a single cycle or multiple cycles comprising administration of BCG without a phagolysosomal escape domain.
- the recombinant Mycobacterium cell is administered as a second-line treatment.
- the individual to be treated may have received a first treatment, in particular of bladder carcinoma treatment, selected from the group of standard BCG treatment, chemotherapy including systemic and/or intravesical chemotherapy, bladder surgery, radiation and any combination thereof.
- the first-line treatment may include cisplatin-based chemotherapy, in particular cisplatin-based chemotherapy followed by bladder surgery and/or radiation therapy, concomitant chemotherapy and standard BCG.
- the individual to be treated has received standard BCG treatment as a first treatment of bladder carcinoma and/or underwent cystectomy or another local treatment or systemic chemotherapy.
- the subject to be treated according to the present invention is suffering from bladder carcinoma, particularly non-muscle invasive bladder carcinoma (NMIBC) including carcinoma in situ (CIS).
- NMIBC non-muscle invasive bladder carcinoma
- CIS carcinoma in situ
- the subject is suffering from recurrent NMBIC.
- the subject has a recurrent high-grade NMIBC for progression (e.g., score 7-23) based on the European Organization for Research and Treatment.
- the subject has undergone to a transurethral resection of the bladder tumor (TURBT) before therapy start.
- the subject has a tumor-free bladder state at therapy start, e.g., as confirmed by transurethral resection of the bladder (TURB) and biopsy.
- the subject is a patient with a high grade NMIBC tumor present at 6 months or both at 3 months and 6 months after start of a previous cycle of standard BCG therapy and worsening of the disease under standard BCG therapy including at least one of higher number of recurrences, higher tumor category or higher grade, and appearances of CIS, including low grade tumors, optionally in spite of an initial response.
- the subject is a smoker.
- a recombinant Mycobacterium cell as described herein as a second-line therapy is highly effective in reducing disease occurrence for an extended time period, e.g., a time period of at least 1 year, particularly for a time period of at least 2 years, of at least 3 years or of at least 4 years after treatment start. 3 years after treatment start, the median time of disease recurrence is already 1.3 years and will probably increase further. At this time, no tumor recurrence was observed in about 49% of the patients.
- the therapy of the present invention provides a disease-free time period of at least 1 year, particularly of at least 2 years, of at least 3 years, or of at least 4 years for at least 30% of the patients and particularly for at least 45% of the patients.
- the treatment is highly efficient in stopping disease recurrence in a sub-group of patients, who did not suffer from disease recurrence in a time period up to 2 years after treatment start.
- administration of a recombinant Mycobacterium cell as described herein is highly effective in increasing the overall survival in an extended time period, e.g., a time period of at least 1 year, particularly in a time period of at least 2 years, of at least 3 years or of at least 4 years. 3 years after start of the treatment, the overall survival rate was between 70% and 80%.
- the therapy of the invention is suitable in avoiding cystectomy in a large number of patients resulting in a high improvement of life quality.
- cystectomy may be avoided for a time period of at least a 1 year, particularly for a time period of at least 2 years, of at least 3 years or of at least 4 years in at least 30% of the patients and particularly for at least 45% of the patients.
- the immunotherapeutic agent is a live recombinant Mycobacterium cell, which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide comprising (a) a domain capable of eliciting an immune response and (b) a phagolysosomal escape domain.
- the domain capable of eliciting an immune response is preferably an immunogenic peptide or polypeptide from a pathogen or an immunogenic fragment thereof.
- the Mycobacterium cell is preferably an M. bovis cell, an M. tuberculosis cell, particularly an attenuated M. tuberculosis cell or other Mycobacteria, e.g. M. microti, M. smegmatis, M. canettii, M. marinum or M. fortuitum. More preferably, the cell is an attenuated recombinant M. bovis (BCG) cell, particularly an M. bovis BCG cell, more particularly a recombinant M. bovis BCG cell from strain Danish subtype Prague (Brosch et al., Proc. Natl. Acad. Sci. USA, 104 (2007), 5396-5601).
- BCG attenuated recombinant M. bovis
- the Mycobacterium cell is recombinant urease-deficient.
- the ureC sequence of the Mycobacterium cell is inactivated (AUrec), e.g., by constructing a suicide vector containing a ureC gene disrupted by a selection marker gene, e.g., the hygromycin gene, transforming the target cell with the vector and screening for selection marker-positive cells having a urease negative phenotype.
- the selection marker gene i.e. , the hygromycin gene, is subsequently inactivated.
- the cell is a selection marker-free recombinant Mycobacterium cell.
- the cell is selection marker-free recombinant BCG strain Danish subtype Prague characterized as recombinant BCG AUrec::Hly+.
- the domain capable of eliciting an immune response is preferably selected from immunogenic peptides or polypeptides from M. bovis, M. tuberculosis or M. leprae or from immunogenic fragments thereof having a length of at least 6, preferably at least 8 amino acids, more preferably at least 9 amino acids and e.g., up to 20 amino acids.
- suitable antigens are Ag85B (p30) from M. tuberculosis, Ag85B (a-antigen) from M. bovis BCG, Ag85A from M.
- the domain capable of eliciting an immune response is selected from non-Mycobacterium polypeptides. More preferably, the immunogenic domain is derived from the antigen Ag85B. Most preferably, the immunogenic domain comprises the sequence from aa. 41 to aa.51 in SEQ ID No.2.
- the recombinant nucleic acid molecule further comprises a phagolysosomal escape domain, i.e., a polypeptide domain which provides for an escape of the fusion polypeptide from the phagolysosome into the cytosol of mammalian cells.
- a phagolysosomal escape domain i.e., a polypeptide domain which provides for an escape of the fusion polypeptide from the phagolysosome into the cytosol of mammalian cells.
- the phagolysosomal escape domain is a Listeria phagolysosomal escape domain, which is described in US 5,733,151, herein incorporated by reference. More preferably, the phagolysosomal escape domain is derived from the listeriolysin gene (Hly) of L. monocytogenes.
- the phagolysosomal domain is encoded by a nucleic acid molecule selected from: (a) a nucleotide sequence comprising nucleotides 211 - 1722 as shown in SEQ ID No.1, (b) a nucleotide sequence which encodes the same amino acid sequence as the sequence from (a), and (c) a nucleotide sequence hybridizing under stringent conditions with the sequence from (a) or (b).
- a nucleic acid molecule selected from: (a) a nucleotide sequence comprising nucleotides 211 - 1722 as shown in SEQ ID No.1, (b) a nucleotide sequence which encodes the same amino acid sequence as the sequence from (a), and (c) a nucleotide sequence hybridizing under stringent conditions with the sequence from (a) or (b).
- the present invention also comprises nucleic acid sequences hybridizing therewith.
- hybridization is used as defined in Sambrook et al. (Molecular Cloning. A laboratory manual, Cold Spring Harbor Laboratory Press (1989), 1.101 -1.104).
- hybridization is used if a positive hybridization signal can still be observed after washing for one hour with 1 X SSC and 0.1 % SDS at 55°C, preferably at 62° C and more preferably at 68°C, particularly for 1 hour in 0.2 X SSC and 0.1 % SDS at 55°C, preferably at 62°C and more preferably at 68°C.
- a sequence hybridizing with a nucleotide sequence as per SEQ ID No.1 under such washing conditions is a phagolysosomal escape domain encoding nucleotide sequence preferred by the subject invention.
- a nucleotide sequence encoding a phagolysosomal escape domain as described above may be directly obtained from a Listeria organism or from any recombinant source e.g., a recombinant E.coli cell containing the corresponding Listeria nucleic acid molecule, or a variant thereof as described above.
- the recombinant nucleic acid molecule encoding for a fusion polypeptide contains a signal peptide encoding sequence.
- the signal sequence is a signal sequence active in Mycobacteria, preferably in M. bovis, e.g., a native M. bovis signal sequence.
- a preferred example of a suitable signal sequence is the nucleotide sequence coding for the Ag85B signal peptide, which is depicted in SEQ ID No.1 from nucleotide 1 to 120.
- a peptide linker be provided between the immunogenic domain and the phagolysosomal escape domain.
- said peptide linker has a length of from 5 to 50 amino acids. More preferably, a sequence encoding a linker as shown in SEQ ID No.1 from nucleotide 154 to 210 or a sequence corresponding thereto as regards the degeneration of the genetic code.
- the nucleic acid may be located on a recombinant vector.
- the recombinant vector is a prokaryotic vector, i.e. , a vector containing elements for replication or/and genomic integration in prokaryotic cells.
- the recombinant vector carries the nucleic acid molecule of the present invention operatively linked with an expression control sequence.
- the expression control sequence is preferably an expression control sequence active in Mycobacteria, particularly in M. bovis.
- the vector can be an extrachromosomal vector or a vector suitable for integration into the chromosome. Examples of such vectors are known to the man skilled in the art and, for instance, given in Sambrook et at. supra.
- the immunotherapeutic agent of the present invention is suitable for the treatment of bladder carcinoma, e.g., non-invasive bladder carcinoma, e.g. non-invasive papillary carcinoma in situ (T a ), non-invasive carcinoma in situ (Tcis), tumor invading subepithelial connective tissue (Ti), tumor invading superficial muscle (inner half) ⁇ h a ), tumor invading deep muscle (outer half) (T 2b ), tumor invading perivesical tissue (T3 including T3a and T3 b ), tumor invading prostate, uterus or vagina (T4a), and tumor invading pelvic wall or abdominal wall (T4 b ).
- non-invasive bladder carcinoma e.g. non-invasive papillary carcinoma in situ (T a ), non-invasive carcinoma in situ (Tcis), tumor invading subepithelial connective tissue (Ti), tumor invading superficial muscle (inner half) ⁇ h a ), tumor invading
- the tumor is a superficial tumor or carcinoma in situ (Tcis), non-invasive papillary carcinoma (T a ), or a tumor invading subepithelial connective tissue (Ti).
- the immunotherapeutic treatment is suitable in the treatment of primary bladder carcinoma and/or in the treatment of recurring bladder carcinoma.
- the immunotherapeutic agent is locally administered to the tumor site, i.e., to the site of a primary tumor before surgery or after surgery and optionally after chemotherapy.
- the agent is preferably administered by vesicular instillation into the urinary bladder.
- the immunotherapeutic agent is administered to the subject to be treated in an effective dose.
- the dose for an administration may be about 10 6 to 10 10 viable units (CFU), e.g., about 10 7 to 5 x 10 9 or 10 8 to 3 x 10 9 viable units.
- the dose for an administration is about 2 x 10 9 viable units (CFU).
- the immunotherapeutic agent is administered several times, e.g., at least 3 times or at least 5 times up to 30 times, particularly about 15 times, at predetermined times during the treatment.
- the immunotherapeutic agent is usually provided as a pharmaceutical preparation, which comprises the recombinant Mycobacterial cell in solid form, e.g., a lyophilized or cryoconserved preparation, which is reconstituted with a suitable liquid carrier before use.
- a pharmaceutical preparation which comprises the recombinant Mycobacterial cell in solid form, e.g., a lyophilized or cryoconserved preparation, which is reconstituted with a suitable liquid carrier before use.
- the preparation may be provided in liquid form, e.g., as suspension.
- the immunotherapeutic agent of the invention is administered for the treatment of carcinoma in situ.
- a standard schedule may comprise weekly administration of the agent for at least 4, e.g., 4, 5, 6, 7 or 8 weeks as an induction therapy.
- the induction therapy should not start until 2- 3 weeks after primary tumor surgery.
- administration may continue using maintenance therapy for at least 6 months or at least 1 year.
- the immunotherapeutic agent is administered in an induction therapy in the prophylactic treatment of tumor recurrence.
- therapy may start about 2-3 weeks after biopsy of the tumor site and be repeated, e.g., at weekly intervals for at least 4, e.g., 4, 5, 6, 7 or 8 weeks. In intermediate and high-risk tumors this may be followed by maintenance therapy.
- Maintenance therapy may comprise long-term therapy, e.g., 6, 9 or 12 months therapy or even longer with treatments at monthly intervals.
- maintenance therapy may comprise 2, 3 or 4 administrations at weekly intervals, at month 3, 6, 12, 18, 24, 30 and 36.
- the immunotherapeutic agent is used for the treatment of non-muscle invasive bladder cancer in patients with recurrence after standard BCG therapy.
- the immunotherapeutic agent is administered into the bladder according to a schedule involving weekly instillations during an induction phase with e.g., 6 weekly instillations, a first maintenance phase after about 3 months with e.g., 3 weekly instillations, a second maintenance phase after about 6 months with e.g., 3 instillations and a third maintenance phase after about 12 months with e.g., 3 instillations.
- the administration as immunotherapeutic agent of the recombinant Mycobacterium cell as described above may be combined with further anti tumor therapy, e.g., radiation and/or chemotherapy. Further, the immunotherapy as described above may be combined with a non-tumor site specific administration of the recombinant Mycobacterium cell in order to provide a general stimulation of the immune system. This non-site specific administration may be effected as described in WO 2012/085101 , e.g., before surgery of the primary tumor.
- the agent is preferably administered to a human subject in a dose of about 1-10 x 10 5 , preferably about 2-8 x 10 5 cells.
- the agent is preferably administered as a single dose, e.g., by injection. Subcutaneous injection is preferred. Further, it is preferred to administer the agent without adjuvant.
- rBCG recombinant M. bovis (BCG) Danish subtype Prague with an inactivated ureC sequence (AUrec) and without functional selection marker gene which expresses an Ag85B/Flly fusion protein as shown in SEQ ID No.2 (Hly+).
- BCG recombinant M. bovis
- AUrec inactivated ureC sequence
- Example 1 Phase I/ll open label clinical trial assessing safety and efficacy of intravesical instillation of recombinant BCG (rBCG) in human patients with recurrent non-muscle invasive bladder cancer after standard BCG therapy
- Phase I Phase I was conducted to determine safety, tolerability, and the recommended phase II dose of intravesical rBCG instillations in patients with recurrence of non-muscle-invasive bladder cancer after TURB and standard BCG therapy.
- Phase II was conducted to investigate the efficacy, safety, tolerability and immunogenicity of intravesical rBCG instillations in patients with recurrence of non-muscle-invasive bladder cancer after TURB in standard BCG therapy.
- Clinical protocol rBCG was administered into bladder in 15 weekly instillations (induction phase: instillations 1-6; maintenance 3 months: instillations 7-9; maintenance 6 months: instillations 10-12, maintenance 12 months: instillations 13-15).
- the primary endpoint of the phase I was dose limiting toxicity (DLT) of intravesical rBCG instillations in patients with recurrence after standard BCG therapy in non-muscle invasive bladder cancer (NMIBC).
- DLT dose limiting toxicity
- NMIBC non-muscle invasive bladder cancer
- the DLT period corresponds to 3 instillations plus 1 week and covers acute toxicities induced by treatment.
- Patients were treated in two cohorts of three, following the rules of a 3 + 3 design (dose de-escalation rules: if patients treated at dose level 1 show signs of DLT, dose of instilled rBCG will be reduced to level -1 , which is 10 times lower than level 1 ).
- the dose levels were as follows:
- progression score 7-2 - Recurrent high-grade NMIBC for progression (progression score 7-23) based on the European Organization for Research and Treatment of Cancer scoring system, failing BCG therapy (Babjuk M, Eur Urol 2008 PMID 18468779), for whom radical cystectomy or re-induction with standard BCG is indicated.
- UC urothelial carcinoma
- Phase II was conducted with dose level 1: 1- 19.2 x 10 8 CFU of rBCG.
- the active agent was administered in 50 ml drug solution containing dextran, glucose, 0.9% sodium chloride, 0.025% Tween 80 and water for injection.
- the treatment was safe and well tolerated, with only 5% of patients unable to tolerate adequate induction therapy. No dose-limiting toxicity occurred and no grade 3 or 4 adverse events were observed.
- the trial was designed as a multicentre, open-label, single-arm, phase I/ll study and conducted in compliance with the current version of the declaration of Helsinki, the ICH-GCP, and with national legal and regulatory requirements. Written informed consent was obtained from all patients prior to enrolment.
- Prior therapy was defined as one previous cycle of intravesical BCG (induction phase >5 instillations ⁇ BCG maintenance).
- bladder wash cytology had to be negative, except for patients with pure or concomitant CIS and imaging without evidence of metastatic disease.
- Exclusion criteria were stage > T2 urothelial carcinoma of the bladder, concomitant urothelial carcinoma of the upper urinary tract, the non-prostatic urethra, or evidence of metastatic disease
- rBCG was provided as a formulated lyophilized powder of 1-19.2 c 10 8 CFU/vial of live Mycobacterium bovis BCG ureCwhly (SIIPL, Serum Institute of India Private Limited, Pune, India) and reconstituted in 50 ml of 0.9% saline water for intravesical application. Patients were scheduled for standard treatment of 6 weekly intravesical instillations followed by maintenance of 1 year (3 instillations at 3, 6 and 12 months after first instillation).
- the primary endpoint of the phase II part was defined as the recurrence-free rate (RFR) in the bladder 60 weeks after registration.
- RFR recurrence-free rate
- a recurrence in the bladder associated with cancer in the prostatic urethra or evidence for cancer in the upper urinary tract were not considered as a recurrence in the bladder.
- Predefined secondary endpoints included time from trial registration to recurrence in the bladder, time to progression, overall survival (OS), AEs, tolerability, and QoL.
- Progression was defined as progression to muscle-invasive bladder cancer or progression to metastatic disease.
- OS was calculated from registration until death from any cause.
- Tolerability was defined as the proportion of patients finishing five instillations of induction within 12 weeks after treatment start. 2.1.2 Statistical analyses
- a history of chemical exposure as a risk factor for bladder cancer was identified in 3 patients, while 21 patients (52.5%) had a smoking history with a median (range) of 38 (4.0-99.0) pack-years. Concomitant or pure CIS was present in 27 (67.5%) patients. Fourteen patients (35%) received BCG maintenance therapy. The median progression score was 16 (7-20) for those patients with and 16 (7-19) for those without previous BCG maintenance.
- progression-free rate and OS rate were 76.3% [95% Cl 56.4, 88.0] and 92.9% [95% Cl 74.3, 98.2], respectively.
- Treatment-related AEs are listed in Table 6.
- the major grade 2 AE term was genitourinary tract infection with common uropathogenic bacteria in one third of the patients. Two patients had to undergo in-hospital antibiotic treatment for urogenital tract infection.
- GU infection The most common AE was genitourinary (GU) infection with common bacteria, occurring in one third of the patients. Potential explanations are i) that lubricants containing antiseptics for instillations were not allowed, and ii) that asymptomatic patients with positive urine dipstick had to undergo antibiotic treatment when urine culture was positive. Importantly, the GU infections did not significantly impact on QoL of the patients (not shown). No grade 4 or 5 AE occurred, and tolerability (defined as patients receiving more than 4 instillations during induction) was 95.2%. The treatment can therefore be considered as safe and well tolerated.
- rBCG has the potential to decrease the proportion of patients becoming intolerable to BCG treatment and may be combined with other agents such as check-point inhibitors in order to increase efficiency.
- rBCG has a promising tolerability, safety, and QoL profile.
- BCG Bacillus Calmette Guerin. Some patients received more than one treatment. One of the 13 patients undergoing cystectomy received surgery due to chronic bladder infection and not because of cancer recurrence.
- Figure 1 Kaplan Meier plot for time to recurrence in the bladder after a follow- up time up to 2.9 years.
- Figure 4 Kaplan Meier plot for time to recurrence in the bladder for the FAS (follow up to 4 years).
- sequences listed as SEQ ID N0.1 and SEQ ID NO.2 are as follows:
- SEQ ID NO. 1 Nucleotide sequence encoding a phagolysosomal domain (nt 211-1722) and a stop codon (nt 1879-1881) atgacagacg tgagccgaaa gattcgagct tggggacgcc gattgatgat cggcacggca gcggctgtag tccttccggg cctggtgggggg cttgccggcg gagcggcaac cgcgggcgcg ttctccggc cggc cggc cggc cggggc c cggggcgagtac ctgcagtctg caaagcaatc cgctgcaaat aaattgcact cagcaggaca aaaattgcact cagcaggaca aaaattgcact cag
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PCT/EP2022/070373 WO2023001895A1 (en) | 2021-07-22 | 2022-07-20 | Recombinant mycobacterium as an immunotherapeutic agent for the second-line therapy of bladder carcinoma |
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AU (1) | AU2022313491A1 (en) |
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2022
- 2022-07-20 IL IL310225A patent/IL310225A/en unknown
- 2022-07-20 AU AU2022313491A patent/AU2022313491A1/en active Pending
- 2022-07-20 EP EP22751731.5A patent/EP4373519A1/en active Pending
- 2022-07-20 CA CA3224671A patent/CA3224671A1/en active Pending
- 2022-07-20 WO PCT/EP2022/070373 patent/WO2023001895A1/en active Application Filing
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CA3224671A1 (en) | 2023-01-26 |
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