US20160317634A1 - Novel msln targeting dna vaccine for cancer immunotherapy - Google Patents
Novel msln targeting dna vaccine for cancer immunotherapy Download PDFInfo
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- US20160317634A1 US20160317634A1 US15/105,739 US201415105739A US2016317634A1 US 20160317634 A1 US20160317634 A1 US 20160317634A1 US 201415105739 A US201415105739 A US 201415105739A US 2016317634 A1 US2016317634 A1 US 2016317634A1
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- salmonella
- mutant strain
- attenuated mutant
- msln
- attenuated
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- C—CHEMISTRY; METALLURGY
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- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
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Definitions
- the present invention relates to an attenuated mutant strain of Salmonella comprising a recombinant DNA molecule encoding Mesothelin.
- the present invention relates to the use of said attenuated mutant strain of Salmonella in cancer immunotherapy.
- Mesothelin is a glycosyl-phosphatidylinositol anchored glycoprotein present on the cell surface of various human solid tumors. Mesothelin was first identified with the monoclonal antibody (mAb)K1 (Chang et al., 1992).
- the Mesothelin (MSLN) gene encodes a 71-kDa precursor protein that is processed to a 40-kDa glycosyl-phosphatidylinositol anchored protein, the mature portion to which mAB K1 binds, termed Mesothelin, and a NH2-terminal 31-kDa fragment called megakaryocyte-potentiating factor that is released from the cell.
- Mesothelin is a tumor differentiation antigen present at low levels on a restricted set of normal adult tissues, such as mesothelium, but aberrantly overexpressed in mesotheliomas, ovarian and pancreatic cancers (Hassan et al., 2004).
- MSLN is a promising candidate for the development of cancer vaccines.
- MSLN Mesothelin
- Hassan et al. Clin Cancer Res, 2004
- Several immunotherapeutic approaches have been used to target MSLN overexpressing tumor types.
- Hassan et al. (Clin Cancer Res, 2004) discloses anti-mesothelin immunotoxin SS1P [SS1(dsFv)PE38] exhibiting antitumor activity in adult nude mice.
- Attenuated derivatives of Salmonella enterica are attractive vehicles for the delivery of heterologous antigens to the mammalian immune system, since S. enterica strains can potentially be delivered via mucosal routes of immunization, i.e. orally or nasally, which offers advantages of simplicity and safety compared to parenteral administration. Furthermore, Salmonella strains elicit strong humoral and cellular immune responses at the level of both systemic and mucosal compartments. Batch preparation costs are relatively low and formulations of live bacterial vaccines are highly stable. Attenuation can be accomplished by deletion of various genes, including virulence, regulatory, and metabolic genes.
- Salmonella typhimurium strains attenuated by aro mutations have been shown to be safe and effective delivery vehicles for heterologous antigens in animal models.
- Salmonella enterica serovar strain namely Salmonella enterica serovar typhi Ty21a (short: S. typhi Ty21a), which has been accepted for use in humans and is distributed under the trade name of Vivotif® (Berna Biotech Ltd., a Crucell Company, Switzerland; marketing authorization number PL 15747/0001 dated 16 Dec. 1996).
- WO 2013/091898 discloses a method for growing attenuated mutant Salmonella typhi strains lacking galactose epimerase activity and harboring a recombinant DNA molecule.
- MSLN is a promising tumor antigen for the development of cancer vaccines.
- Major limitations of previously available MSLN vaccines are the administration via the intravenous route of administration and the associated side effects.
- the great need for improved cancer therapy approaches based on targeting MSLN has not been met so far.
- the present invention relates to an attenuated mutant strain of Salmonella comprising at least one copy of a recombinant DNA molecule comprising an expression cassette encoding Mesothelin (MSLN).
- MSLN Mesothelin
- the attenuated Salmonella strain of the present invention was shown to elicit a strong immune response in healthy mice. To the inventor's knowledge, this novel attenuated Salmonella strain is the first oral cancer vaccine targeting MSLN. Since MSLN is overexpressed in mesotheliomas, ovarian and pancreatic cancers, and a wide variety of other tumors, the attenuated Salmonella strain of the present invention has great potential as cancer vaccine for the treatment of these indications.
- the vaccine according to the present invention (VXM04) has been demonstrated to elicit a strong MSLN-specific immune response in healthy mice. These results indicate that vaccination with VXM04 may lead to an immune response and the development of an immune memory against tumor cells overexpressing MSLN. It is remarkable and surprising that the novel vaccine VXM04 is effective at relatively low doses.
- the attenuated Salmonella mutant strain of the present invention may be applied in monotherapy or in combination with a second attenuated mutant strain of Salmonella comprising a DNA molecule encoding a second tumor antigen. Furthermore, the attenuated mutant strain of the present invention may be administered in combination with chemotherapy, radiotherapy or biological cancer therapy. Treatment with VXM04 may also be effective, if the patient has developed a resistance to chemotherapy (chemo-refractory patients).
- the novel attenuated Salmonella strain of the present invention might therefore be useful in novel, greatly improved cancer therapy approaches.
- the attenuated mutant strain of Salmonella is of the species Salmonella enterica .
- the attenuated mutant strain of Salmonella is Salmonella typhi Ty21a.
- the expression cassette is a eukaryotic expression cassette.
- MSLN is selected from the group consisting of human MSLN and a protein that shares at least about 80% sequence identity therewith.
- the MSLN has the amino acid sequence as found in SEQ ID NO 1.
- the recombinant DNA molecule comprises the kanamycin antibiotic resistance gene, the pMB1 ori, and a eukaryotic expression cassette encoding human MSLN or a protein that shares at least 80% sequence identity therewith under the control of a CMV promoter.
- human MSLN has the nucleic acid sequence as found in SEQ ID NO 2.
- the attenuated mutant strain of Salmonella is for use as a medicament.
- the attenuated mutant strain of Salmonella is for use as a vaccine.
- the attenuated mutant strain of Salmonella is for use in cancer immunotherapy.
- cancer immunotherapy further comprises administration of one or more further attenuated mutant strain(s) of Salmonella comprising at least one copy of a recombinant DNA molecule comprising an expression cassette encoding a tumor antigen and/or a tumor stroma antigen.
- said one or more further attenuated mutant strain(s) of Salmonella is/are Salmonella typhi Ty21a comprising a eukaryotic expression cassette.
- said one or more further strain(s) of Salmonella comprise(s) an attenuated mutant strain(s) of Salmonella encoding the tumor stroma antigen human VEGFR-2 and/or the tumor antigen human Wilms' Tumor Protein (WT1).
- the attenuated mutant strain of Salmonella is co-administered with said one or more further attenuated mutant strain(s) of Salmonella.
- cancer immunotherapy is accompanied by chemotherapy, radiotherapy or biological cancer therapy.
- the attenuated mutant strain of Salmonella is administered during the chemotherapy or the radiotherapy treatment cycle or during biological cancer therapy.
- the attenuated mutant strain of Salmonella is administered before the chemotherapy or the radiotherapy treatment cycle or before biological cancer therapy.
- the attenuated mutant strain of Salmonella is administered after the chemotherapy or the radiotherapy treatment cycle or after biological cancer therapy.
- the attenuated mutant strain of Salmonella is administered before and during at least one of the chemotherapy, the radiotherapy treatment cycle and the biological cancer therapy.
- the attenuated mutant strain of Salmonella may be administered before or during or before and during at least one of these therapies, particularly during at least two of these therapies.
- the attenuated mutant strain of Salmonella is administered orally.
- the cancer is selected from mesotheliomas, ovarian and pancreatic cancers, squamous cell carcinomas of the cervix, head and neck, vulva, lung and esophagus, lung adenocarcinomas, endometrial carcinomas, biphasic synovial sarcomas, desmoplastic small round cell tumors and gastric adenocarcinomas.
- the single dose is from about 10 5 to about 10 11 , particularly from about 10 6 to about 10 10 , more particularly from about 10 6 to about 10 9 , more particularly from about 10 6 to about 10 8 , most particularly from about 10 6 to about 10 7 colony forming units (CFU).
- CFU colony forming units
- the attenuated mutant strain of Salmonella is for use in personalized cancer immunotherapy comprising the step of assessing the MSLN expression pattern and/or the pre-immune response against MSLN of a patient.
- the present invention relates to an attenuated mutant strain of Salmonella comprising at least one copy of a recombinant DNA molecule comprising an expression cassette encoding Mesothelin (MSLN).
- MSLN Mesothelin
- the attenuated Salmonella strain functions as the bacterial carrier of the recombinant DNA molecule comprising an expression cassette encoding Mesothelin (MSLN) for the delivery of said recombinant DNA molecule into a target cell.
- MSLN Mesothelin
- the term “attenuated” refers to a bacterial strain of reduced virulence compared to the parental bacterial strain, not harboring the attenuating mutation. Attenuated bacterial strains have preferably lost their virulence but retained their ability to induce protective immunity. Attenuation can be accomplished by deletion of various genes, including virulence, regulatory, and metabolic genes. Attenuated bacteria may be found naturally or they may be produced artificially in the laboratory, for example by adaptation to a new medium or cell culture or they may be produced by recombinant DNA technology.
- mutant strain refers to a bacterial strain harboring a mutation in its genome.
- mutation refers to a change in a nucleic acid sequence, including point mutations, insertions, deletions, translocations and inversions.
- the term “comprises” or “comprising” means “including, but not limited to”.
- the term is intended to be open-ended, to specify the presence of any stated features, elements, integers, steps or components, but not to preclude the presence or addition of one or more other features, elements, integers, steps, components or groups thereof.
- the term “comprising” thus includes the more restrictive terms “consisting of” and “essentially consisting of”.
- the term “comprising” as used throughout the application and in particular within the claims may be replaced by the term “consisting of”.
- the term “recombinant DNA molecule” refers to an engineered DNA construct, preferably composed of DNA pieces of different origin.
- the recombinant DNA molecule can be a linear nucleic acid, or preferably, a circular recombinant DNA plasmid generated by introducing an open reading frame encoding MSLN into an expression vector plasmid.
- expression cassette refers to a nucleic acid unit comprising at least the MSLN gene under the control of regulatory sequences controlling its expression.
- the expression cassette comprised in the attenuated mutant strain of Salmonella can preferably mediate transcription of the included open reading frame encoding MSLN in a target cell.
- Expression cassettes typically comprise a promoter, at least one open reading frame and a transcription termination signal.
- Mesothelin is a 40-kDa cell surface glycoprotein present on normal mesothelial cells and overexpressed in several human tumors, including mesothelioma and ovarian and pancreatic adenocarcinoma.
- the mesothelin gene encodes a precursor protein of 71-kDa that is processed to yield a 31-kDa shed protein named megakaryocyte-potentiating factor (MPF) and the 40-kDa cell bound fragment mesothelin.
- MPF megakaryocyte-potentiating factor
- Mesothelin was shown to exhibit megakaryocyte-colony-forming activity in the presence of interleukin-3.
- Mesothelin is a tumor differentiation antigen present at low levels on a restricted set of normal adult tissues, such as mesothelium, but aberrantly overexpressed in a wide variety of human tumors including mesotheliomas, ovarian and pancreatic cancers, squamous cell carcinomas of the cervix, head and neck, vulva, lung and esophagus, lung adenocarcinomas, endometrial carcinomas, biphasic synovial sarcomas, desmoplastic small round cell tumors and gastric adenocarcinomas.
- the normal biological function of Mesothelin is unknown.
- mesothelin knock-out mice revealed no detectable phenotype, and both male and female mice produced healthy off-spring.
- Studies in pancreatic cancer suggest that mesothelin plays a role in tumorigenesis by increasing cellular proliferation, migration, and S-phase cell populations.
- mesothelin is an immunogenic protein. Due to its expression profile, its oncogenic functions and its immunogenic potential, the tumor antigen mesothelin is a promising candidate for the development of cancer vaccines.
- Mesothelin is a tumor differentiation antigen present at low levels on a restricted set of normal adult tissues, such as mesothelium, but aberrantly overexpressed in mesotheliomas, ovarian and pancreatic cancers (Hassan et al., 2004).
- MSLN is a promising candidate for the development of cancer vaccines.
- the attenuated mutant strain of Salmonella is of the species Salmonella enterica .
- the attenuated mutant strain of Salmonella is Salmonella typhi Ty21a.
- the attenuated S. typhi Ty21a strain is the active component of Typhoral L®, also known as Vivotif® (manufactured by Berna Biotech Ltd., a Crucell Company, Switzerland). It is currently the only licensed live oral vaccine against typhoid fever. This vaccine has been extensively tested and has proved to be safe regarding patient toxicity as well as transmission to third parties (Wandan et al., J. Infectious Diseases 1982, 145:292-295). The vaccine is licensed in more than 40 countries.
- the Marketing Authorization number of Typhoral L® is PL 15747/0001 dated 16 Dec. 1996.
- One dose of vaccine contains at least 2 ⁇ 10 9 viable S. typhi Ty21a colony forming units and at least 5 ⁇ 10 9 non-viable S. typhi Ty21a cells.
- Salmonella typhi Ty21a bacterial strain One of the biochemical properties of the Salmonella typhi Ty21a bacterial strain is its inability to metabolize galactose. The attenuated bacterial strain is also not able to reduce sulfate to sulfide which differentiates it from the wild-type Salmonella typhi Ty2 strain. With regard to its serological characteristics, the Salmonella typhi Ty21a strain contains the 09-antigen which is a polysaccharide of the outer membrane of the bacteria and lacks the 05-antigen which is in turn a characteristic component of Salmonella typhimurium . This serological characteristic supports the rationale for including the respective test in a panel of identity tests for batch release.
- the expression cassette is a eukaryotic expression cassette.
- the term “eukaryotic expression cassette” refers to an expression cassette which allows for expression of the open reading frame in a eukaryotic cell. It has been shown that the amount of heterologous antigen required to induce an adequate immune response may be toxic for the bacterium and result in cell death, over-attenuation or loss of expression of the heterologous antigen. Using a eukaryotic expression cassette that is not expressed in the bacterial vector but only in the target cell may overcome this toxicity problem and the protein expressed may exhibit a eukaryotic glycosylation pattern.
- a eukaryotic expression cassette comprises regulatory sequences that are able to control the expression of an open reading frame in a eukaryotic cell, preferably a promoter and a polyadenylation signal. Promoters and polyadenylation signals included in the recombinant DNA molecules comprised by the attenuated mutant strain of Salmonella of the present invention are preferably selected to be functional within the cells of the subject to be immunized.
- Suitable promoters include but are not limited to promoters from Cytomegalovirus (CMV), such as the strong CMV immediate early promoter, Simian Virus 40 (SV40), Mouse Mammary Tumor Virus (MMTV), Human Immunodeficiency Virus (HIV), such as the HIV Long Terminal Repeat (LTR) promoter, Moloney virus, Epstein Barr Virus (EBV), and from Rous Sarcoma Virus (RSV) as well as promoters from human genes such as human actin, human myosin, human hemoglobin, human muscle creatine, and human metallothionein.
- CMV promoter refers to the strong immediate-early cytomegalovirus promoter.
- suitable polyadenylation signals include but are not limited to the bovine growth hormone (BGH) polyadenylation site, SV40 polyadenylation signals and LTR polyadenylation signals.
- BGH bovine growth hormone
- the eukaryotic expression cassette included in the recombinant DNA molecule comprised by the attenuated mutant strain of Salmonella of the present invention comprises the BGH polyadenylation site.
- heterologous MSLN gene like a promoter and a polyadenylation signal
- additional elements include enhancers.
- the enhancer can be, for example, the enhancer of human actin, human myosin, human hemoglobin, human muscle creatine and viral enhancers such as those from CMV, RSV and EBV.
- regulatory sequences and codons are generally species dependent, so in order to maximize protein production, the regulatory sequences and codons are preferably selected to be effective in the species to be immunized.
- the person skilled in the art can produce recombinant DNA molecules that are functional in a given subject species.
- MSLN is selected from the group consisting of human MSLN and a protein that shares at least about 80% sequence identity therewith.
- the term “about” or “approximately” means within 80% to 120%, alternatively within 90% to 110%, including within 95% to 105% of a given value or range.
- the term “protein that shares at least about 80% sequence identity with human MSLN” refers to a protein that differs in the amino acid sequence and/or the nucleic acid sequence encoding the amino acid sequence of human MSLN.
- the protein may be of natural origin, e.g. a homolog of MSLN of a different species, or an engineered protein, e.g. an engineered MSLN derivative. It is known that the usage of codons is different between species. Thus, when expressing a heterologous protein in a target cell, it may be necessary, or at least helpful, to adapt the nucleic acid sequence to the codon usage of the target cell.
- Methods for designing and constructing derivatives of a given protein are well known to anyone of ordinary skill in the art.
- the protein that shares at least about 80% sequence identity with human MSLN may contain one or more mutations comprising an addition, a deletion and/or a substitution of one or more amino acids.
- said deleted, added and/or substituted amino acids may be consecutive amino acids or may be interspersed over the length of the amino acid sequence of the protein that shares at least about 80% sequence identity with human MSLN.
- any number of amino acids may be added, deleted, and/or substitutes, as long as the sequence identity with human MSLN is at least about 80%.
- the sequence identity with human MSLN is at least about 80%, at least about 85%, at least about 90%, or most particularly at least about 95%.
- nucleic acid sequences encoding the protein that shares at least about 80% sequence identity with human MSLN may differ to a larger extent due to the degeneracy of the genetic code.
- MSLN has the amino acid sequence as found in SEQ ID NO 1.
- the recombinant DNA molecule comprises the kanamycin antibiotic resistance gene, the pMB1 ori, and a eukaryotic expression cassette encoding human MSLN or a protein that shares at least 80% sequence identity therewith under the control of a CMV promoter.
- human MSLN has the nucleic acid sequence as found in SEQ ID NO 2.
- the recombinant DNA molecule is derived from commercially available pVAX1TM expression plasmid (Invitrogen, San Diego, Calif.).
- This expression vector was modified by replacing the high copy pUC origin of replication by the low copy pMB1 origin of replication of pBR322. The low copy modification was made in order to reduce the metabolic burden and to render the construct more stable.
- the generated expression vector backbone was designated pVAX10. Inserting human MSLN with the nucleic acid sequence as found in SEQ ID NO 2 into this expression vector backbone via NheI/XhoI yielded the expression plasmid pVAX10.hMSLN.
- the expression plasmid pVAX10.hMSLN is schematically depicted in FIG. 3 .
- the attenuated mutant strain of Salmonella is for use as a medicament.
- the attenuated mutant strain of Salmonella is for use as a vaccine.
- the term “vaccine” refers to an agent which is able to induce an immune response in a subject upon administration.
- a vaccine can preferably prevent, ameliorate or treat a disease.
- a vaccine in accordance with the present invention comprises an attenuated mutant strain of Salmonella , preferably S. typhi Ty21a.
- the vaccine in accordance with the present invention further comprises at least one copy of a recombinant DNA molecule comprising an expression cassette, preferably a eukaryotic expression cassette, encoding MSLN, preferably selected from human MSLN or a protein that shares at least about 80% sequence identity therewith.
- the live attenuated Salmonella mutant strain according to the present invention comprising a recombinant DNA molecule encoding MSLN can be used as a vehicle for the oral delivery of this recombinant DNA molecule.
- a delivery vector comprising a DNA molecule encoding a heterologous antigen, such as MSLN, is termed DNA vaccine.
- Genetic immunization might be advantageous over conventional vaccination.
- the target DNA can be detected for a considerable period of time thus acting as a depot of the antigen.
- Sequence motifs in some plasmids like GpC islands, are immunostimulatory and can function as adjuvants furthered by the immunostimulation due to LPS and other bacterial components.
- Live bacterial vectors produce their own immunomodulatory factors such as lipopolysaccharides (LPS) in situ which may constitute an advantage over other forms of administration such as microencapsulation.
- LPS lipopolysaccharides
- the use of the natural route of entry proves to be of benefit since many bacteria, like Salmonella , egress from the gut lumen via the M cells of Peyer's patches and migrate eventually into the lymph nodes and spleen, thus allowing targeting of vaccines to inductive sites of the immune system.
- the vaccine strain of Salmonella typhi , Ty21a has been demonstrated to-date to have an excellent safety profile.
- the bacteria Upon exit from the gut lumen via the M cells, the bacteria are taken up by phagocytic cells, such as macrophages and dendritic cells.
- Attenuated derivatives of Salmonella enterica are attractive as vehicles for the delivery of heterologous antigens to the mammalian immune system because S. enterica strains can potentially be delivered via mucosal routes of immunization, i.e. orally or nasally, which offers advantages of simplicity and safety compared to parenteral administration. Furthermore, Salmonella strains elicit strong humoral and cellular immune responses at the level of both systemic and mucosal compartments.
- the attenuated mutant strain of Salmonella is for use in cancer immunotherapy.
- cancer immunotherapy further comprises administration of one or more further attenuated mutant strain(s) of Salmonella comprising at least one copy of a recombinant DNA molecule comprising an expression cassette encoding a tumor antigen and/or a tumor stroma antigen.
- said one or more further mutant strain(s) of Salmonella is/are Salmonella typhi Ty21a comprising a eukaryotic expression cassette.
- said one or more further strain(s) of Salmonella comprise(s) an attenuated mutant strain of Salmonella encoding human VEGFR-2 and/or human Wilms' Tumor Protein (WT1).
- Combining the attenuated mutant strain of Salmonella of the present invention with a second attenuated mutant strain comprising a DNA molecule encoding a second tumor antigen may have synergistic antitumor effects.
- simultaneous targeting of different tumor antigens may minimize the risk of tumor escape.
- Combining MSLN based cancer immunotherapy with VEGFR-2 based immunotherapy may prove especially effective, since MSLN overexpressing tumor cells and the tumor vasculature are attacked at the same time.
- the attenuated mutant strain of Salmonella is co-administered with said one or more further attenuated mutant strain(s) of Salmonella.
- co-administration means administration of two different attenuated mutant strains of Salmonella within three consecutive days, more particularly within two consecutive days, more particularly on the same day, more particularly within 12 hours. Most particularly, in the context of the present invention, the term “co-administration” refers to simultaneous administration of two different attenuated mutant strains of Salmonella.
- cancer immunotherapy is accompanied by chemotherapy, radiotherapy or biological cancer therapy.
- complete eradication of cancer stem cells may be essential.
- maximal efficacy a combination of different therapy approaches may be beneficial.
- biological cancer therapy refers to cancer therapy involving the use of living organisms, substances derived from living organisms, or laboratory-produced versions of such substances.
- Some biological therapies for cancer aim at stimulating the body's immune system to act against cancer cells (so called biological cancer immunotherapy).
- Biological cancer therapy approaches include the delivery of tumor antigens, delivery of therapeutic antibodies as drugs, administration of immunostimulatory cytokines and administration of immune cells.
- Therapeutic antibodies include antibodies targeting tumor antigens or tumor stroma antigens as well as antibodies functioning as checkpoint inhibitors, such as anti-PD-1, anti-PD-L1 and anti-CTLA4.
- Chemotherapeutic agents that may be used in combination with the attenuated mutant strain of Salmonella of the present invention may be, for example: gemcitabine, amifostine (ethyol), cabazitaxel, cisplatin, dacarbazine (DTIC), dactinomycin, docetaxel, mechlorethamine, streptozocin, cyclophosphamide, carrnustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), doxorubicin lipo (doxil), folinic acid, gemcitabine (gemzar), daunorubicin, daunorubicin lipo (daunoxome), procarbazine, ketokonazole, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil (5-FU), vinblastine, vincristine, bleomycin, paclitaxel (taxol), docetaxel
- chemotherapeutic agents according to the invention in combination with VXM04 are cabazitaxel, carboplatin, oxaliplatin, cisplatin, cyclophosphamide, docetaxel, gemcitabine, doxorubicin, paclitaxel (taxol), irinotecan, vincristine, vinblastine, vinorelbin, folinic acid, 5-fluorouracil and bleomycin, especially gemcitabine.
- Treatment options for fever, anaphylaxis, blood pressure instability, bronchospasm, and dyspnoea are available.
- Treatment options in case of unwanted T-cell derived auto-aggression are derived from standard treatment schemes in acute and chronic graft vs. host disease applied after stem cell transplantation. Cyclosporin and glucocorticoids are proposed as treatment options.
- antibiotic therapy is recommended, for example with fluoroquinolones including ciprofloxacin or ofloxacin.
- Bacterial infections of the gastrointestinal tract are to be treated with respective agents, such as rifaximin.
- the attenuated mutant strain of Salmonella is administered during the chemotherapy or the radiotherapy treatment cycle or during biological cancer therapy.
- the attenuated mutant strain of Salmonella is administered before the chemotherapy or the radiotherapy treatment cycle or before biological cancer therapy.
- This approach may have the advantage that chemotherapy or radiotherapy can be performed under conditions of enhanced cancer immunity.
- the attenuated mutant strain of Salmonella is administered after the chemotherapy or the radiotherapy treatment cycle or after biological cancer therapy.
- the attenuated mutant strain of Salmonella is administered orally. Oral administration is simpler, safer and more comfortable than parenteral administration.
- intravenous administration of live bacterial vaccines such as the Listeria monocytogenes based mesothelin vaccine described in Dung et al., (Clin Cancer Res, 2012) initially causes a bacteremia associated with safety risks of the sepsis-type.
- intravenous administration of live bacterial vaccines calls for careful observation and monitoring of clinical symptoms such as cytokine release.
- Oral administration of the attenuated mutant strain of the present invention may at least in part overcome the described risks.
- the attenuated mutant strain of Salmonella of the present invention may also be administered by any other suitable route.
- a therapeutically effective dose is administered to the subject, and this dose depends on the particular application, the type of malignancy, the subject's weight, age, sex and state of health, the manner of administration and the formulation, etc. Administration may be single or multiple, as required.
- the attenuated mutant strain of Salmonella of the present invention may be provided in the form of a solution, a suspension, lyophilisate, or any other suitable form. It may be provided in combination with pharmaceutically acceptable carriers, diluents, and/or excipients. Agents for adjusting the pH value, buffers, agents for adjusting toxicity, and the like may also be included.
- pharmaceutically acceptable refers to molecular entities and other ingredients of pharmaceutical compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human).
- pharmaceutically acceptable may also mean approved by a regulatory agency of a Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and, more particularly, in humans.
- the cancer is selected from mesotheliomas, ovarian and pancreatic cancers, squamous cell carcinomas of the cervix, head and neck, vulva, lung and esophagus, lung adenocarcinomas, endometrial carcinomas, biphasic synovial sarcomas, desmoplastic small round cell tumors and gastric adenocarcinomas.
- the vaccine of the present invention is surprisingly effective at relatively low doses.
- the single dose is from about 10 5 to about 10 11 , particularly from about 10 6 to about 10 10 , more particularly from about 10 6 to about 10 9 , more particularly from about 10 6 to about 10 8 , most particularly from about 10 6 to about 10 7 colony forming units (CFU).
- Administration of low doses of this live bacterial vaccine minimizes the risk of excretion and thus of transmission to third parties.
- the term “about” or “approximately” means within a factor of 3, alternatively within a factor of 2, including within a factor of 1.5 of a given value or range.
- the attenuated mutant strain of Salmonella is for use in individualized cancer immunotherapy comprising the step of assessing the MSLN expression pattern and/or the pre-immune response against MSLN of a patient.
- VXM04 can be used—either by itself or in combination with other Salmonella typhi Ty21a based cancer vaccines comprising eukaryotic expression systems—for the treatment of various cancer types.
- VXM04 may be used for individualized patient specific cancer treatment.
- the patient's tumor and/or stromal antigen expression pattern and/or the patient's pre-immune responses against tumor and/or stromal antigens may be assessed in a first step for example by companion diagnostics targeting the patient's specific tumor and/or stromal antigen pattern.
- VMX04 may be administered either alone or in combination with one or more suitable further Salmonella typhi Ty21a based cancer vaccine(s) comprising eukaryotic expression systems.
- Combinations of VXM04 with one or more further Salmonella typhi Ty21a based cancer vaccine(s) may however also be administered as fixed combinations. These cocktails combining two or more Salmonella typhi Ty21a based cancer vaccines can be composed from separate off the shelf products.
- the combinations, either fixed or individualized may contain VXM01 (WO 2013/091898) as anti-angiogenic basis therapy.
- FIG. 1 Amino acid sequence of human MSLN encoded by MSLN cDNA contained in plasmid pVAX10.hMSLN
- FIG. 2 Nucleic acid sequence of pVAX10.hMSLN
- FIG. 3 Plasmid map of pVAX10.hMSLN
- FIG. 4 Percentages of Meso-specific CD8+ cells in spleens from healthy C57Bl/6 mice as detected by MSLN-GSL-Penta. Individual percentages of the entirety of mice treated with VXM-04m-empty in comparison to the entirety of mice treated with VXM-04m are shown.
- FIG. 5 Percentages of Meso-specific CD8+ cells in spleens from healthy C57Bl/6 mice as detected by MSLN-GSL-Penta. Individual percentages partitioned according to the treatment groups are shown.
- FIG. 6 Percentages of Meso-specific CD8+ cells in spleens from healthy C57Bl/6 mice as detected by MSLN-GSL-Penta. Individual percentages partitioned according to the treatment groups are shown.
- FIG. 7 Percentages of Meso-specific CD8+ cells in spleens from healthy C57Bl/6 mice as detected by MSLN-IQL-Penta. Individual percentages of the entirety of mice treated with VXM-04m-empty in comparison to the entirety of mice treated with VXM-04m are shown.
- FIG. 8 Percentages of Meso-specific CD8+ cells in spleens from healthy C57Bl/6 mice as detected by MSLN-IQL-Penta. Individual percentages partitioned according to the treatment groups are shown.
- FIG. 9 Percentages of Meso-specific CD8+ cells in spleens from healthy C57Bl/6 mice as detected by MSLN-IQL-Penta. Individual percentages partitioned according to the treatment groups are shown.
- Human MSLN (1893 bp, MSLN sequence according to NCBI reference sequence NM_013404.4) and murine MSLN (1878 bp, MSLN sequence according to NCBI reference sequence NM_018857.1) were cloned into the pVAX10 backbone derived of pVAX10.VR2-1.
- MSLN DNA fragments were generated by double-strand gene synthesis, where oligonucleotides were linked together using a thermostable ligase. The obtained ligation products were amplified by PCR.
- the in vitro synthesized DNA fragments of human and murine MSLN were cloned into the pVAX10 backbone via NheI/XhoI (the VEGFR-2 coding region of recombinant plasmid pVAX10.VR2-1 was replaced by human or murine MSLN).
- NheI/XhoI the VEGFR-2 coding region of recombinant plasmid pVAX10.VR2-1 was replaced by human or murine MSLN.
- the entire plasmids were sequenced and aligned to the respective reference sequence after transformation into E. coli . Both sequences proved to be free of errors.
- the resulting plasmids were designated pVAX10.mMSLN and pVAX10.hMSLN.
- S. typhi Ty 21a was transformed with plasmid pVAX10.hMSLN.
- S. typhimurium SL7207 (aroA ⁇ ) was transformed with plasmid pVAX10.mMSLN. The transformation was performed by electroporation.
- Glycerol cultures of S. typhi Ty21a and S. typhimurium SL7207 were inoculated on LB plates (animal component free [ACF] soy peptone). The plates were incubated at 37° C. overnight. One colony each was used for overnight-liquid-preculture. 3 ml LB medium (ACF soy peptone) inoculated with one colony each was incubated at 37° C. and 180 rpm overnight. To prepare competent cells, 2 ⁇ 300 ml of LB medium (ACF soy peptone) were inoculated with 3 ml of the overnight culture and incubated at 37° C. and 180 rpm up to an OD 600 of about 0.5.
- the cultures were then put on ice for 10 minutes. Subsequently, the bacteria were centrifuged for 10 minutes at 3000 ⁇ g at 4° C. and each pellet was resuspended in 500 mL of ice cold H 2 O dest , After a new centrifugation step, the bacterial pellets were washed twice in 10% ice cold glycerol. Both pallets were put together in 2 ml of 10% glycerol and finally frozen in aliquots of 50 ⁇ L on dry ice. The used glycerol did not contain any animal ingredients (Sigma Aldrich, G5150).
- a 50 ⁇ l aliquot of competent cells was thawed on ice for 10 minutes. After adding 3-5 ⁇ L of plasmid DNA (pVAX10.hMSLN for competent S. typhi Ty21a cells and pVAX10.mMSLN for competent S. typhimurium SL7207 cells) the mixtures were incubated on ice for five minutes. Subsequently, the mixtures were transferred to pre-cooled cuvettes (1 mm thickness). The electric pulse was carried out at 12.5 kV/cm.
- LB medium ACF soy peptone
- 1 ml of LB medium ACF soy peptone
- the cells were transferred into a 2 ml Eppendorf tube and shaken for 1 hour at 37° C.
- a short centrifugation step on a bench centrifuge (16600 rcf, 20 s)
- the bacterial pellet was resuspended in 200 ⁇ l of LB (ACF soy peptone) antibiotic-free medium.
- 3 ml of liquid LB-Kan medium (ACF soy peptone) were inoculated with one colony of recombinant Salmonella ( S. typhi Ty21a harboring pVAX10.hMSLN and S. typhimurium SL7207 harboring pVAX10.mMSLN) and incubated overnight at 37° C. and 180 rpm. The overnight culture was pelleted by centrifugation at 1300 rpm for 30 s on a bench centrifuge (Biofuge pico, Heraeus). The plasmid isolation was performed with the NucleoSpin Plasmid Kit from Macherey-Nagel.
- the plasmid DNA was loaded onto columns with a silica membrane. After a washing step, the plasmids were eluted from the column with 50 ⁇ l of sterile water and sequenced. The sequences were then compared with the respective reference sequence by clone specific alignments, i.e. the plasmid sequences of each Salmonella clone was one by one aligned with the reference sequence. All sequences were in line with the respective reference sequences.
- the recombinant Salmonella strains were designated VXM04 ( S. typhi Ty21a harboring plasmid pVAX10.hMSLN) and VXM04m ( S. typhimurium SL7207 harboring plasmid pVAX10.mMSLN).
- a positive pressure (20 ⁇ 4 Pa) was maintained in the experimentation room to prevent contamination or the spread of pathogens within a rodent colony.
- Animals were housed in polycarbonate cages (Techniplast, Limonest, France) that were equipped to provide food and water. The standard area cages used were 800 cm 2 with a maximum of 10 mice per cage (from the same group).
- Bedding for animals was sterile corn cob bedding (ref: LAB COB 12, SERLAB, Cergy-Pontoise, France), replaced twice a week. Animal wood was purchased from DIETEX (Saint-Gratien, France). Irradiated RM1 was used as sterile controlled granules.
- mice from groups 1 to 5 received administrations of VXM04m-empty, the animals from groups 6 to 10 received administrations of VXM04m. Both VXM04m-empty and VXM04m were thawed and administered within 30 min, the working solutions were discarded after use.
- the treatment dose of VXM04m-empty and VXM04m was 10 10 CFU in 100 ⁇ l per administration.
- VXM04m-empty and VXM04m were administered by oral gavage (per os, PO) via a cannula with a volume of 0.1 ml. Regardless of animal groups, each animal received pre-dose application buffer to neutralize acid in the stomach prior dosing (100 ⁇ l/animal/application).
- buffer was composed by dissolution of 2.6 g sodium hydrogen carbonate, 1.7 g L-Ascorbic acid, 0.2 g lactose monohydrate in 100 ml of drinking water and was applied within 30 min prior application of VXM04m-empty and VXM04m.
- the treatment schedule was as follows:
- mice from groups 1 to 5 received daily PO administrations of VXM04m-empty at 10 10 in CFU every two days for four consecutive times (Q2D ⁇ 4).
- mice from groups 6 to 10 received daily PO administrations of VXM04m at 10 10 in CFU every two days for four consecutive times (Q2D ⁇ 4).
- mice were terminated after 5 (groups 1 and 6), 7 (groups 2 and 7), 10 (groups 3 and 8), 14 (groups 4 and 9) and 21 (groups 5 and 10) days post vaccination phase (5 mice per animal group and time point).
- Isoflurane (Baxter, France) was used to anaesthetize the animals before termination. Animals were terminated by cervical dislocation. An autopsy (macroscopic examination of heart, lungs, liver, spleen, kidneys and gastrointestinal tract) was performed on all terminated animals. At the time of mice termination, spleens were collected and placed individually into single ID labeled tubes containing chilled PBS (2-8° C.) each and stored over night at 2-8° C. Freshly isolated and purified splenocytes were used for Pentamer analysis. Freshly prepared CD8+ cells were used for ELISpot analysis.
- Splenocyte preparation was performed as follows: In a washing step a part of the PBS was discarded and replaced by fresh PBS. A 100 ⁇ m nylon Cell Strainer (BD Falcon) was hung into the opening of a 50 ml Falcon containing 5 ml 1 ⁇ PBS. The spleens were cut with a scalpel and then pushed through the cell strainer with the stamp of a 5 ml syringe. One strainer was used per spleen, the strainer was always rinsed in between with sterile 1 ⁇ PBS. The cells were centrifuged at 1,500 rpm (approximately 450 g) for 10 min at 2-8° C. and the supernatant was discarded.
- BD Falcon nylon Cell Strainer
- 1 ml ACK-Ery-Lysis buffer (8.3 g/l NH 4 , 1 g/l KHCO 3 , 0.037 g/l EDTA; pH 7.2-7.4) was added per spleen to lyse the red blood cells. The solution was incubated for 30 sec at RT. 10 ml of PBS were added and the cells were again spun down at 1,500 rpm for 10 min at 2-8° C., the supernatant was discarded. The pellet was resuspended in 10 ml DMEM media. Live/dead cell staining was performed with trypan blue and the cell number was counted. The cell suspension was split for the subsequent analyses. About one third was used for Pentamer analysis, the rest was used for the ELISpot analysis.
- Pentamer Analysis included a viability staining and the Pentamer staining.
- one vial of the fluorescent reactive dye Pacific Orange—component A
- the vial of anhydrous DMSO component B
- 50 ⁇ l of DMSO component B
- the well was mixed and it was confirmed visually that all of the dye had dissolved.
- the solution of reactive dye was used without delay, within a few hours of reconstitution.
- the suspension of cells containing at least 1 ⁇ 10 6 cells was centrifuged and the supernatant was discarded.
- the cells were washed once with 1 ml of PBS and resuspended in 1 ml of PBS. The cells were counted and the density was adjusted with PBS to 1 ⁇ 10 6 cells in a 1 ml volume. 1 ⁇ l of the reconstituted fluorescent reactive dye was added to 1 ml of the cell suspension. The suspension was then mixed thoroughly and incubated at room temperature for 30 min, protected from light. The cells were washed once with 1 ml of PBS with 1% Fetal Calf Serum (FCS) and resuspended in 1 ml of PBS with 1% FCS.
- FCS Fetal Calf Serum
- Pro5® Pentamers were centrifuged in chilled microcentrifuge at 14,000 ⁇ g for 5-10 minutes to collect any protein aggregates present in the solution at the bottom of the vial in order to avoid non-specific staining. The supernatant was used for Pentamer staining. All reagents were maintained on ice, shielded form light, until required. 1 ⁇ 10 6 splenocytes were allocated per staining condition. The cells were washed with 2 ml wash buffer (PBS with 1% FCS) and spun down (500 ⁇ g for 5 minutes), the supernatant was discarded and the cells were resuspended in the residual volume ( ⁇ 50 ⁇ l). The tubes were kept chilled on ice for all subsequent steps, except where otherwise indicated.
- PBS wash buffer
- FCS 1% FCS
- Pentamer staining 2 ⁇ l was added to the cells and the solution was mixed by pipetting and incubated at room temperature (22° C.) for 10 min, shielded from light. The cells were then washed with 2 ml wash buffer and resuspended in the residual liquid ( ⁇ 50 ⁇ l). Pro5® Fluorotag R-PE was spun in a chilled microcentrifuge at 14,000 ⁇ g for 3 minutes to remove protein aggregates that would otherwise contribute to non-specific binding. The reagents were maintained on ice, shielded from light, until required. The supernatant was used for Pentamer staining.
- FIGS. 4 to 6 represent Meso-specific CD8+ cells detected by MSLN-GSL-Penta;
- FIGS. 7 to 9 represent Meso-specific CD8+ cells detected by MSLN-IQL-Penta.
- the Immune kinetics peaked at 10 days post-vaccination.
- the percentage of Meso-specific CD8+ cells on day 10 was significantly increased compared to the control group, irrespective of the used Pentamers.
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US20160068801A1 (en) * | 2013-04-25 | 2016-03-10 | Vaximm Ag | Salmonella-based vectors for cancer immunotherapy targeting wilms' tumor gene wt1 |
US9919037B2 (en) | 2013-01-15 | 2018-03-20 | Memorial Sloan Kettering Cancer Center | Immunogenic WT-1 peptides and methods of use thereof |
US10100087B2 (en) | 2012-01-13 | 2018-10-16 | Memorial Sloan Kettering Cancer Center | Immunogenic WT-1 peptides and methods of use thereof |
US10221224B2 (en) | 2005-10-17 | 2019-03-05 | Memorial Sloan Kettering Cancer Center | WT1 HLA class II-binding peptides and compositions and methods comprising same |
US10441645B2 (en) | 2013-12-18 | 2019-10-15 | Vaximm Gmbh | MSLN targeting DNA vaccine for cancer immunotherapy |
US10815273B2 (en) | 2013-01-15 | 2020-10-27 | Memorial Sloan Kettering Cancer Center | Immunogenic WT-1 peptides and methods of use thereof |
US11414457B2 (en) | 2006-04-10 | 2022-08-16 | Memorial Sloan Kettering Cancer Center | Immunogenic WT-1 peptides and methods of use thereof |
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EP3484503A1 (en) * | 2016-07-13 | 2019-05-22 | Vaximm AG | Process for the production of a dna vaccine for cancer immunotherapy |
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DK3082850T3 (da) | 2013-12-18 | 2019-10-07 | Vaximm Gmbh | Msln-targeteret dna-vaccine til cancerimmunterapi |
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US20120076752A1 (en) * | 2002-07-12 | 2012-03-29 | The Johns Hopkins University | Mesothelin Vaccines and Model Systems |
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US10221224B2 (en) | 2005-10-17 | 2019-03-05 | Memorial Sloan Kettering Cancer Center | WT1 HLA class II-binding peptides and compositions and methods comprising same |
US11548924B2 (en) | 2005-10-17 | 2023-01-10 | Memorial Sloan Kettering Cancer Center | WT1 HLA class II-binding peptides and compositions and methods comprising same |
US11414457B2 (en) | 2006-04-10 | 2022-08-16 | Memorial Sloan Kettering Cancer Center | Immunogenic WT-1 peptides and methods of use thereof |
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US10815274B2 (en) | 2012-01-13 | 2020-10-27 | Memorial Sloan Kettering Cancer Center | Immunogenic WT-1 peptides and methods of use thereof |
US10815273B2 (en) | 2013-01-15 | 2020-10-27 | Memorial Sloan Kettering Cancer Center | Immunogenic WT-1 peptides and methods of use thereof |
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US11859015B2 (en) | 2013-01-15 | 2024-01-02 | Memorial Sloan Kettering Cancer Center | Immunogenic WT-1 peptides and methods of use thereof |
US20160068801A1 (en) * | 2013-04-25 | 2016-03-10 | Vaximm Ag | Salmonella-based vectors for cancer immunotherapy targeting wilms' tumor gene wt1 |
US10815455B2 (en) | 2013-04-25 | 2020-10-27 | Vaximm Ag | Salmonella-based vectors for cancer immunotherapy targeting Wilms' tumor gene WT1 |
US9920297B2 (en) * | 2013-04-25 | 2018-03-20 | Vaximm Ag | Salmonella-based vectors for cancer immunotherapy targeting wilms' tumor gene WT1 |
US10441645B2 (en) | 2013-12-18 | 2019-10-15 | Vaximm Gmbh | MSLN targeting DNA vaccine for cancer immunotherapy |
US11986517B2 (en) | 2017-12-13 | 2024-05-21 | Inovio Pharmaceuticals, Inc. | Cancer vaccines targeting mesothelin and uses thereof |
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CN106061500A (zh) | 2016-10-26 |
PL3082850T3 (pl) | 2020-01-31 |
SI3082850T1 (sl) | 2020-01-31 |
US10441645B2 (en) | 2019-10-15 |
JP2017502692A (ja) | 2017-01-26 |
CA2932388A1 (en) | 2015-06-25 |
BR112016014405A2 (pt) | 2018-02-20 |
IL246170B (en) | 2019-06-30 |
KR20160130979A (ko) | 2016-11-15 |
WO2015090584A1 (en) | 2015-06-25 |
RU2016129044A (ru) | 2018-01-23 |
AU2014365900B2 (en) | 2020-04-09 |
MX2016007939A (es) | 2016-10-28 |
HUE045567T2 (hu) | 2020-01-28 |
IL246170A0 (en) | 2016-07-31 |
EP3082850A1 (en) | 2016-10-26 |
EP3082850B1 (en) | 2019-08-28 |
AU2014365900A1 (en) | 2016-07-14 |
LT3082850T (lt) | 2019-11-11 |
SG11201604911VA (en) | 2016-07-28 |
JP6662787B2 (ja) | 2020-03-11 |
DK3082850T3 (da) | 2019-10-07 |
ES2747772T3 (es) | 2020-03-11 |
US20180064794A1 (en) | 2018-03-08 |
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