WO2024089244A2 - Thérapie - Google Patents

Thérapie Download PDF

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WO2024089244A2
WO2024089244A2 PCT/EP2023/080070 EP2023080070W WO2024089244A2 WO 2024089244 A2 WO2024089244 A2 WO 2024089244A2 EP 2023080070 W EP2023080070 W EP 2023080070W WO 2024089244 A2 WO2024089244 A2 WO 2024089244A2
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patient
antibody
specific
cancer
tgfb
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PCT/EP2023/080070
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English (en)
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WO2024089244A3 (fr
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Mads Hald Andersen
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Io Biotech Aps
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Publication of WO2024089244A3 publication Critical patent/WO2024089244A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1841—Transforming growth factor [TGF]
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/00113—Growth factors
    • A61K39/001134—Transforming growth factor [TGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
    • 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2

Definitions

  • the present invention is concerned with identifying cancer patients for which treatment with PD-1/PD-L1 antibodies will be particularly effective.
  • the present invention is further concerned with ways to increase the effectiveness of PD-1/PD-L1 antibody treatment for a given group of cancer patients.
  • the present invention is also concerned with compositions and methods for treating cancer.
  • the present invention provides a way to improve treatment with PD-1/PD-L1 antibodies, particularly for cancer types that are refractory to treatment with such antibodies.
  • the invention is based on the finding that the presence or absence of a TGF-beta specific T cell response is indicative of how effective treatment with PD-1/PD-L1 antibody will be and also, if such a response is present, the magnitude of the response is also indicative of how effective treatment will be.
  • the present invention therefore identifies a patient group for which treatment with PD-1/PD-L1 antibody will be particularly effective. It also allows for the use of TGFbeta or immunogenic peptides from TGFbeta to stimulate, or boost, a TGF- beta T cell response and hence increase the likely efficacy of PD-1/PD-L1 antibody treatment for cancer.
  • the invention is particularly effective for cancers that are refractory to treatment with PD-1/PD-L1 antibody such as pancreatic cancer.
  • a PD-1/PD-L1 antibody which may be employed in the invention is Nivolumab.
  • the antibody is Nivolumab and the cancer is pancreatic cancer.
  • a particularly useful indicator is the presence, and size if present, of a T cell response against the TGFbeta- 15 peptide sequence of SEQ ID NO: 28.
  • the present invention provides a PD-1/PD-L1 antibody for use in a method of treating a cancer in a patient, wherein the method comprises administering the PD- 1/PD-L1 antibody to said patient, wherein the patient has been previously identified as having a TGFbeta-specific T cell response.
  • the present invention further provides a method of treating cancer in a patient, the method comprising administering a PD-1/PD-L1 antibody to said patient, wherein the patient has been previously identified as having a TGFbeta-specific T cell response.
  • the present invention also provides a method of stratifying a patient with cancer into one of at least two treatment groups, the method comprising: i. performing an assay on a sample previously obtained from the patient to detect the presence or absence of a TGFb-specific T cell response; ii. allocating the patient to a first treatment group if a TGFb-specific response is present or stratifying the patient into a second treatment group if a TGFb-specific response is absent; wherein if the patient is allocated to the first treatment group they are to be administered with a PD-l/PD-Ll antibody.
  • the present invention also provides a method of stratifying a patient with cancer into one of at least two treatment groups, the method comprising: i. performing an assay on a sample previously obtained from the patient to detect the level of a TGFb-specific T cell response, if present; ii. allocating the patient to a first treatment group if the TGFb-specific T cell response is at least a threshold value for a TGFb-specific T cell and stratifying the patient into a second treatment group if a TGFb-specific response is below the threshold value; wherein if the patient is allocated to the first treatment group they are to be administered with a PD-l/PD-Ll antibody.
  • the present invention also provides a PD-1/PD-L1 antibody for use in a method of treating cancer, wherein the method comprises:
  • TGFb human transforming growth factor
  • the present invention further provides an immunogenic fragment of human transforming growth factor b (TGFb) for use in a method of treating a cancer in a patient, the method comprising
  • TGFb human transforming growth factor b
  • FIG. 1 TGFb-15 specific responses in pancreatic cancer (PC) patients.
  • PBMCs Peripheral blood mononuclear cells
  • IFNy ELISPOTs interferon-gamma enzyme-linked immunosorbent spots
  • the experiments were performed in triplicates with negative control wells left unstimulated.
  • the responses were characterized in 32 samples isolated at baseline (left) and in 31 samples isolated after 4 series of treatment (right).
  • Normalized counts of the data from A comparing the amplitude of response in patients with clinical benefit and response in patients with progressive disease. Normalization was performed by subtracting the mean spot count of the control wells from the mean spot count of peptide stimulated wells. Error bars in A and C depict standard error of the mean and statistics were performed using a paired T-test. Statistics were made using Mann- Whitney test.
  • FIG. 1 The amplitude of TGFb-15 specific immune responses fluctuates over time.
  • C Normalized TGFb-15 specific immune responses analyzed over time (longer than 2 years) in three patients with clinical benefit. Normalization of spot counts was performed as described previously.
  • FIG. 4 Strong TGFb-15 specific responses before treatment initiation predict superior survival.
  • A. Kaplan-Meier curve displaying overall survival in patients with a response above or below the median response amplitude to TGFb-15.
  • B. Kaplan-Meier curve displaying progression free survival in patients with a response above or below the median response amplitude to TGFb-15. Time-to-event analyses were performed using the log-rank test.
  • FIG. 5 Survival analysis in patients based on the amplitude of the TGFb-15 specific response.
  • A. Analysis of overall survival in patients based on the normalized TGF
  • FIG. 6 Correlation between TGFb-15 specific responses and responses to tetanus epitope.
  • A. Normalized responses to TGFb-15 and tetanus responses were plotted and correlation analyzed using simple linear regression.
  • B. Normalized responses to TGFb-15 and influenza responses were plotted and correlation analyzed using simple linear regression.
  • FIG. 7 The amplitude of TGFb-15 specific responses is not coupled to the amplitude of responses to tetanus peptide.
  • A. PBMCs were tested for response to the tetanus epitope “tetanus-long” using in vitro IFNg ELISPOT assays. The amplitude of the normalized tetanus-long specific response was compared between patients with a response above or below the median TGFb-15 specific immune response. Responses against tetanus- long were not analyzed in baseline samples in five patients from the group with a response above the median and in one patient from the group with a response below the median, but in samples acquired within two weeks of baseline. B.
  • Figure 8 Clostridium tetani and Influenza specific responses are not associated with survival.
  • D Kaplan-Meier curve displaying progression free survival in patients with a response above or below the median response amplitude to Cl 8 A2 Flu. Time-to-event analyses were performed using the log-rank test.
  • FIG. 9 Repeated in vitro stimulations of both patient and healthy donor PBMCs with TGFb-15 peptide increase the amplitude of the TGFb-15 specific immune response.
  • A PBMCs from 16 PC patients with a weak TGFb-15 response were cultured in vitro and tested for response to TGFb-15 after one in vitro stimulation with TGFb-15 peptide or after three in vitro stimulations with TGF
  • B Some cultures only received two in vitro stimulations denoted by a black star next to spot count.
  • FIG. 10 Increased distribution free resampling (DFR) responses after repeated stimulations.
  • A Comparison of DFR responses and DFR2x responses after 1 or repeated stimulations in PC patients.
  • B Comparison as in A but in Healthy donors. Statistical analysis was done using the DFR and DFR2x method.
  • FIG. 12 T-cell responses against TGFb-33 in patients with pancreatic cancer receiving radiotherapy and treatment with anti-CTLA-4 and anti-PD-1.
  • Peripheral blood mononuclear cells (PBMCs) from pancreatic cancer patients were stimulated once in vitro with TGFb-33 peptide and IL-2, and incubated for 14 days before plating in interferon-gamma enzyme-linked immunosorbent spots (IFNy ELISPOTs) at a concentration of 2 xlO 5 cells/well with overnight incubation.
  • IFNy ELISPOTs interferon-gamma enzyme-linked immunosorbent spots
  • the experiments were performed in duplicates or triplicates with negative control wells left unstimulated.
  • the responses were characterized in 31 samples isolated at baseline (left) and in 28 samples isolated after 4 series of treatment (right).
  • the figure displays the normalized response amplitude to TGFb-33 which was calculated by subtracting the mean number of spots from negative control wells from the mean number of spots
  • SEQ ID NO: 1 is the amino acid sequence of the full-length precursor of human TGFb-1 (also referred to as the TGFb-1 pre-protein).
  • SEQ ID NO: 2 is the amino acid sequence of the signal peptide of human TGFb-1.
  • SEQ ID NO: 3 is the amino acid sequence of the LAP peptide of human TGFb-1.
  • SEQ ID NO: 4 is the amino acid sequence of mature human TGFb-1.
  • SEQ ID NOs: 5-64 are each an amino acid sequence of a polypeptide fragment derived from human TGFb-1.
  • SEQ ID NO: 65 is the amino acid sequence of the LAP sub-region comprising a high frequency of immunogenic sequences.
  • SEQ ID NO: 66 is the amino acid sequence of the minimal epitope sequence within the TGFb-15 peptide sequence (SEQ ID NO: 28). SEQ ID NO: 66 is also referred to herein as “TGFb-15-15short”. SEQ ID NO: 67 is the amino acid sequence of TGFb-A2-01.
  • polypeptide is used herein in its broadest sense to refer to a compound of two or more subunit amino acids, amino acid analogs, or other peptidomimetics.
  • polypeptide thus includes short peptide sequences and also longer polypeptides and proteins.
  • amino acid refers to either natural and/or unnatural or synthetic amino acids, including both D or L optical isomers, and amino acid analogs and peptidomimetics.
  • patient and “subject” are used interchangeably and typically refer to a human.
  • a polypeptide is capable of eliciting an immune response to the TGFb protein, in particular TGFb-1 protein, typically when said protein is present in or on cells expressing the TGFb-1 protein.
  • the polypeptide may be described as immunogenic to TGFb.
  • the polypeptide may alternatively be described as an immunogenic fragment of TGFb.
  • the immune response may refer to a T cell response, and so the polypeptide may be described as an immunogenic fragment of TGFb comprising a T cell epitope.
  • the immune response may be detected in at least one individual (or in sample taken from the individual) after administration of the polypeptide to said individual (or said sample).
  • TGF-b T-GF-beta, and the like corresponds to reference to TGF- p.
  • the former nomenclature has been used.
  • the present invention is based on the finding that patients displaying a T cell response specific for TGFbeta represent a patient group for which therapy with PD-1/PD-L1 antibody is likely to be particularly effective. Furthermore, it has also been found that the magnitude of the T cell response specific for TGFbeta indicates how effective treatment with PD-1/PD-L1 antibody for cancer is likely to be. That means it is possible to determine the presence or absence of a T cell response specific for TGFbeta, or to quantify it, for a given patient to determine how effective treatment with PD-1/PD-L1 antibody is likely to be. It may be therefore used as a way to determine whether or not to treat a patient with PD-1/PD-L1 antibody.
  • the T cell response specific for TGFbeta may refer to that against TGFbetal.
  • the invention is particularly useful in the context for cancers that are refractory to treatment with PD-1/PD-L1 antibody.
  • the cancer is pancreatic cancer and the antibody is Nivolumab.
  • whether or not a TGFbeta response is present, or the size of the response is measured at “baseline” that is before treatment has begun. It may also be measured during the course of treatment as well. In a further embodiment, whether or not a TGFbeta response is present may be measured at baseline and then after a treatment intended to increase the T cell response for TGFbeta response to check that the response occurred or increased.
  • whether or not a patient has a T cell response specific for TGFbeta at all is measured. It may be that the result for a test sample for the patient is compared to that for a negative control and if there is not a significant increase in the result for the test sample versus the negative control it may be said that a response is lacking. It may be that rather than determining simply the presence or absence of a response, the size of the response is measured, as the present inventors have found that patients with a higher level of response show more positive results with PD-1/PD-L1 antibody.
  • Whether or not a patient has a TGFbeta-specific T cell response, or the size of the response, may be measured by any suitable method. Whether or not such a response is present may be measured by determining whether or not T cells isolated from the patient show a response when exposed to TGFbeta-1 or a TGFbeta-1 peptide.
  • Any of the TGFbeta peptide sequences set out herein may be employed, with an especially preferred peptide of interest being the TGFbeta- 15 peptide sequence of (SEQ ID NO: 28) or TGFbeta short peptide sequence of (SEQ ID NO:66).
  • a further preferred peptide of interest is the TGFbeta- 33 peptide sequence of SEQ ID NO: 55.
  • a patient sample for assessment may be one obtained from blood.
  • Peripheral blood mononuclear cells represent a preferred sample used herein.
  • the cells are purified T cells, for example T cells purified from the blood of the patient.
  • One method for measuring whether or not a subject displays a TGFbeta-specific T cell response is to use peripheral blood mononuclear cells PBMCs isolated from the subject and assay whether or not they show a response to TGFbeta-1 or a TGFbeta-1 peptide.
  • One suitable assay is to incubate the PBMCs with TGFbeta-1 or a TGFbeta-1 peptide, then determine whether or not the cells present are activated by the TGFbeta-1 or a TGFbeta-1 peptide.
  • a possible method for determining whether or not activated T cells show a response to TGFbeta-1 is an ELISPOT assay.
  • the assay employed in the Examples of the present application may be used to determine whether or not a response is present and if it is, to quantify it.
  • an assay comprises: (a) incubating PBMCs isolated from the patient with TGFbeta-1 or a TGFbeta-1 peptide for from 7 to 14 days; (b) plating a known number of cells into plates coated with a primary IFN-y specific antibody, incubating the plate overnight, then removing the cells; (c) detecting the presence of bound IFN-y using secondary antibody, streptavidin- ALP, and enzyme substrate with washing of wells with PBS before and between each step, meaning that the location of an activated cell secreting IFN- y can be identified as a spot; and (d) counting the number of spots and hence the number of cells specific for TGFbeta-1.
  • IL-2 may also be included in the incubation step.
  • the assay may comprise controls, such as also performing a negative control sample where no TGFbeta-1 or a TGFbeta-1 peptide is included in the incubation step of (a).
  • a subject is defined as lacking a T cell response for TGFbeta if it gives the same, or similar, result to a negative control.
  • the absence of a response in an ELISPOT assay may be said to be no more than five times the number of spots in comparison to the equivalent negative control.
  • an assay may further comprise a positive control, for example a sample including T cells that will display a response against TGFbeta.
  • the size of any TGFbeta T cell response is measured.
  • a method may be used which allows the number of T cells producing a TGFbeta-specific response to be enumerated. A way of doing so is to employ a spot-based assays.
  • An ELISpot assay represents an assay used herein. The assay employed in the Examples of the present application may be, for instance, employed.
  • the invention may comprise producing, or comparing to, the value obtained against an expected value. It may be that a patient is selected for treatment on the basis of having a baseline T cell response specific for TGFbeta- 1 that is the same or greater than a threshold value.
  • One way of setting a threshold value is in terms of the median value.
  • the median value may be the median baseline value seen in cancer sufferers, particularly cancer sufferers with the same type of cancer.
  • the median may be calculated from cancer suffers of the same cancer type and gender. It may be calculated from representative samples of such cancer sufferers.
  • the expected median value for a given value may have already been calculated and can be used.
  • another way of setting a threshold value is in terms of the 75th percentile value.
  • the 75th percentile value may be the 75th percentile value of the baseline value seen in cancer sufferers, particularly cancer sufferers with the same type of cancer.
  • the 75th percentile may be calculated from cancer suffers of the same cancer type and gender. It may be calculated from representative samples of such cancer sufferers.
  • the expected 75th percentile value for a given value may have already been calculated and can be used.
  • the invention may involve working out in which percentile the value for a patient falls within the value for a population of patients with the same condition.
  • the invention may be used to give an indication of the likely efficacy of treatment with PD-1/PD-L1 antibody.
  • a “threshold value” may be applied to decide whether or not the subject is given PD-1/PD-L1 antibody.
  • it may be that if the value is below the threshold value then the patient is selected for treatment to increase the TGFbeta-specific T cell response to help improve the likely efficacy of PD-1/PD-L1 antibody.
  • a TGFbeta- 1 peptide, or encoding sequence may be administered to the subject to try and stimulate such a response.
  • the invention may be applied to any suitable mammalian subject, though the patient is human.
  • the patient may be male or female. In one embodiment the patient is male.
  • the patient will have cancer.
  • the cancer is selected from pancreatic cancer, melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction (GEJ) cancer.
  • the patient may have Unresectable or Metastatic Melanoma.
  • the patient may have Metastatic Non-Small Cell Lung Cancer.
  • the patient may have Malignant Pleural Mesothelioma.
  • the patient may have advanced Renal Cell Carcinoma.
  • the patient may have classical Hodgkin Lymphoma. In another embodiment, the patient may have Squamous Cell Carcinoma of the Head and Neck. In another embodiment, the patient may have Urothelial Carcinoma. In a further embodiment, the patient may have Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer. In a further embodiment, the patient may have Hepatocellular Carcinoma. In a further embodiment, the patient may have Esophageal Cancer. In a further embodiment, the patient may have Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma. In one embodiment, the cancer is metastatic cancer. In another embodiment, the cancer is metastatic cancer with two or less metastases.
  • the cancer is a cancer that is refractory to treatment with PD- 1/PD-L1 antibody.
  • An example of such a refractory cancer is pancreatic cancer.
  • the subject may therefore have pancreatic cancer.
  • the pancreatic cancer is metastatic cancer.
  • the cancer is refractory metastatic pancreatic cancer (mPC).
  • a PD-1/PD-L1 antibody is typically one that blocks the interaction between PD-1 and PD-L1. Hence, in one embodiment the antibody binds PD-1. In another embodiment, the antibody binds PD-L1.
  • PD-1 antibodies include Nivolumab, Pembrolizumab, Cemiplimab, and Dostarlimab.
  • PD-L1 antibodies include Atezolizumab, Avclumab, and Durvalumab.
  • Nivolumab An especially preferred PD-1 antibody of interest is Nivolumab.
  • Nivolumab is sold under the brand name Opdivo®. It may also be sold under the names ONO-4538, BMS- 936558, or MDX1106. Nivolumab may be used to treat a variety of cancers.
  • the patient is administered only PD-1/PD-L1 antibody.
  • PD-1/PD-L1 antibody though is sometimes given in combination with other therapies or as a further line of treatment after treatment with another therapy.
  • it may be that in any of the embodiments set out herein where a subject is given PD-1/PD-L1 antibody that they are also given a second cancer therapy as well.
  • the patient is given both PD-l/PD- L1 antibody and a CTLA-4 antibody.
  • the CTLA-4 antibody is Ipilimumab.
  • the patient is given both PD-1/PD-L1 antibody and radiotherapy.
  • the subject is given PD-1/PD-L1 antibody, CTLA-4 antibody, and radiotherapy.
  • a preferred CTLA-4 antibody is Ipilimumab.
  • a form of radiotherapy is stereotactic body radiotherapy (SBRT).
  • Nivolumab is a PD-1 antibody of interest. Hence, it may be that Nivolumab is administered alone. It may be that Nivolumab is administered with a CTLA-4 antibody (e.g., Ipilimumab). It may be in either case that radiotherapy is administered. Hence, in one embodiment Nivolumab, Ipilimumab, and SBRT are administered.
  • radiotherapy is provided in the form of stereotactic body radiotherapy (SBRT) at about 15 Gy on a single site of disease.
  • SBRT is provided on day 1 of a 14-day treatment cycle.
  • Nivolumab is administered at a dose of about 3 mg/kg (up to a maximum of about 240 mg).
  • Nivolumab is administered intravenously.
  • Nivolumab is administered on day 1 ( ⁇ 3 days) of each 14-day treatment cycle.
  • Ipilimumab is administered at a dose of about 1 mg/kg.
  • Ipilimumab is administered intravenously.
  • Ipilimumab is administered on day 1 of a 14-day treatment cycle, and subsequently once every 6 weeks ( ⁇ 3 days) thereafter.
  • CTLA-4 antibody it may be that a CTLA-4 antibody is given, or that the patient is already being treated with such an antibody.
  • An example of a CTLA-4 antibodies is Ipilimumab sold under the brand name Yervoy®.
  • a further example of a preferred CTLA-4 antibody is Tremelimumab.
  • a TGFbeta-1 peptide as described further herein may be administered to the patient to stimulate such a response.
  • a TGFbeta-1 peptide is administered at a dose of about 200 pg.
  • the TGFbeta-1 peptide may be administered in emulsion with an adjuvant.
  • a TGFbeta-1 peptide is administered at a dose of about 200 pg, in emulsion with about 500 pl Montanide ISA-51.
  • the peptide-adjuvant emulsion may be administered on day 1 of the first 6 14-day treatment cycles and subsequently once every 4 weeks ( ⁇ 3 days) thereafter.
  • an additional agent or therapy are to be given to the patient as well as PD-1/PD-L1 antibody it may be that they are given simultaneously, separately or sequentially.
  • Two drugs may be given in the same composition or in separate compositions.
  • a TGFbeta-1 peptide is given to try and stimulate a TGFbeta-specific T cell response, it may be given prior to the PD-1/PD-L1 antibody.
  • the TGFbeta peptide may be given, the stimulation of a T cell response against TGFbeta may be confirmed, and then PD-1/PD-L1 antibody is given or PD-1/PD-L1 antibody is given once the value of the response increases over a threshold.
  • the TGFbeta- Ipeptide and the PD-1/PD-L1 antibody may be given at the same time.
  • the TGFbeta is typically TGFbeta-1. It may be that TGFbetal sequences are used in terms of whether or not a T cell response against TGFbeta is present in a patient. Alternatively, the sequences discussed below may be used to stimulate such a response.
  • sequence of the full-length human TGFbeta-1 pre-protein (SEQ ID NO: 1) is provided below:
  • GQILSKLRLA SPPSQGEVPP GPLPEAVLAL YNSTRDRVAG ESAEPEPE 110 120 130 140 150
  • Table 1 below sets out various TGFbeta-1 related sequences including specific
  • TGFbeta-1 peptides which may be used in the present invention.
  • Start pos and “End pos” indicate the positions within full length human TGFbeta-1 pre -protein (SEQ ID NO: 1) unless otherwise indicated.
  • a T cell response specific for TGFbeta may be determined using TGFbeta-1 itself or using one of the TGFbeta-1 peptide sequences herein.
  • the TGFbeta- 1 peptide sequences discussed herein may also be used to bring about, or increase the size of a T cell response specific for TGFbeta-1 and so improve the treatment for cancer.
  • the sequences discussed below may be relevant for detecting/measuring TGFbeta- specificT cell response, but also in seeking to stimulate/increase such a response.
  • a peptide sequence is that of the TGFb-15 peptide of SEQ ID NO: 28.
  • a peptide is that of SEQ ID NO: 66.
  • a peptide is that of SEQ ID NO: 55.
  • a preferred TGFbeta-1 peptide sequence for employing in the invention is an immunogenic fragment of human TGFbeta-1 (SEQ ID NO: 1) which comprises or consists of a sequence of at least 9 consecutive amino acids of SEQ ID NO: 1.
  • the sequence of at least 9 consecutive amino acids of SEQ ID NO: 1 may, for instance, correspond to a sequence of at least 9 consecutive amino acids of the signal peptide (SP) domain of TGFbeta-1, for example a sequence of at least 9 consecutive amino acids of SEQ ID NO: 2. It may correspond to a sequence of at least 9 amino acids of the latency-associated peptide (LAP) domain of TGFb- 1, for example at least 9 consecutive amino acids of SEQ ID NO: 3.
  • SP signal peptide
  • LAP latency-associated peptide
  • It may correspond to a sequence of at least 9 consecutive amino acids located within the LAP sub-region bounded by amino acid positions 121 and 160 of SEQ ID NO: 1, for example a sequence of at least 9 consecutive amino acids of SEQ ID NO: 65. It may correspond to a sequence of at least 9 consecutive amino acids of the mature TGFbl polypeptide, for example a sequence of at least 9 consecutive amino acids of SEQ ID NO: 4.
  • the polypeptide may comprise or consist of up to 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45 or 50 consecutive amino acids of SEQ ID NO: 1.
  • the polypeptide may comprise or consist of the amino acid sequence of any one of SEQ ID NOs: 2 and 5-67.
  • the polypeptide may comprise or consist of the amino acid sequence of any one of SEQ ID NOs: 6, 42, 12, 23, 28, 49, 55, 63, 5, 7-9, 43-45, 13-15, 24- 26, 29-31, 50-52, 56-58, 64, 65, 2, 66, 67 or 5.
  • polypeptides comprise or consist of the amino acid sequence of any one of SEQ ID NOs: 6, 42, 12, 23, 28, 49, 55, 63, 66, 67 or 5.
  • polypeptide may comprise or consist of the amino acid sequence of any one of SEQ ID NOs: 28, 66, 29-31, 67, 5-9, 42-45, 12-15, 55-58, 23-26, 49-52, 63, 64, 65 or 2.
  • polypeptides comprise or consist of the amino acid sequence of SEQ ID NOs: 66, 28, 67, 5, 6, 42, 12, 55, 23, 49 or 63.
  • the polypeptide may have a maximum length of 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45 or 50 amino acids.
  • the C terminal amino acid of the polypeptide may be replaced with the corresponding amide.
  • the polypeptide may be isolated.
  • polypeptides comprise or consist of the amino acid sequence of any one of SEQ ID NOs: 6, 42, 12, 23, 28, 49, 55, or 63. In further embodiments, polypeptides comprise or consist of the amino acid sequence of any one of SEQ ID NOs: 66, 28, 67, 5, 6, 42, 12, 55, 23, 49 or 63. Longer polypeptide fragments of SEQ ID NO: 1 which incorporate these sequences may also be employed.
  • the polypeptide may comprise an HLA-A2 restricted epitope.
  • the HL A- A2 -restricted epitope comprises or consists of the amino acid sequence of SEQ ID NO: 66.
  • peptides which comprise an HLA-A2 restricted epitope consisting of the amino acid sequence of SEQ ID NO: 66 are peptides which comprise or consist of the amino acid sequence of any one of SEQ ID NOs: 28-31 or 65.
  • the HL A- A2 -restricted epitope comprises or consists of the amino acid sequence of SEQ ID NO: 67.
  • peptides which comprise a HLA-A2 restricted epitope consisting of the amino acid sequence of SEQ ID NO: 67 are peptides which comprise or consist of the amino acid sequences of any one of SEQ ID NOs: 5, 8, 9 or 2.
  • the amino acid sequence may be modified by one, two, three, four, or five (that is up to five) additions, deletions or substitutions, provided that a polypeptide having the modified sequence exhibits the same or increased immunogenicity to TGFbl, as compared to a polypeptide having the unmodified sequence.
  • a polypeptide having the modified sequence exhibits the same or increased immunogenicity to TGFbl, as compared to a polypeptide having the unmodified sequence.
  • the polypeptide of the modified sequence does not exhibit significantly reduced immunogenicity to TGFbl as compared to polypeptide of the unmodified sequence. Any comparison of immunogenicity between sequences is to be conducted using the same assay. Unless otherwise specified, modifications to a polypeptide sequence are conservative amino acid substitutions.
  • amino acids may have similar polarity, hydrophilicity, hydrophobicity, basicity, acidity, neutrality or charge to the amino acids they replace.
  • conservative substitution may introduce another amino acid that is aromatic or aliphatic in the place of a pre-existing aromatic or aliphatic amino acid.
  • Conservative amino acid changes are well-known in the art and may be selected in accordance with the properties of the 20 main amino acids as defined in Table 2 below. Where amino acids have similar polarity, this can be determined by reference to the hydropathy scale for amino acid side chains in Table 3.
  • any one or more of the following modifications may be made to improve physiochemical properties (e.g. stability), provided that the polypeptide exhibits the same or increased immunogenicity to TGFbl, as compared to a polypeptide having the unmodified sequence: (i) replacement of the C terminal amino acid with the corresponding amide (may increase resistance to carboxypeptidases); (ii) replacement of the N terminal amino acid with the corresponding acylated amino acid (may increase resistance to aminopeptidases); (iii) replacement of one or more amino acids with the corresponding methylated amino acids (may improve proteolytic resistance); and/or (iv) replacement of one or more amino acids with the corresponding amino acid in D- configuration (may improve proteolytic resistance).
  • Preferred peptides that may be employed are set out in WO 2020/245264 Al (PCT/EP2020/065472) the entirety of which is incorporated by reference and the TGFbl sequences disclosed therein are also specifically incorporated by reference, both in relation to potential epitopes the T cell response may be against, but also as sequences used to stimulate such a response.
  • a sequence encoding such a peptide may be administered instead, as may be a composition comprising a peptide or encoding sequence.
  • compositions comprising polypeptides
  • the present invention provides for use of TGFbl peptides set out herein to increase, or bring about, a TGFbeta-specific T cell response, where the subject is also administered with a PD-1/PD-L1 antibody.
  • the TGFbetal peptide may be provided in the form of a pharmaceutical composition for use in such methods.
  • the composition may also comprise a PD-1/PD-L1 antibody.
  • the present invention also provides a PD-1/PD-L1 antibody for use as set out herein and the PD-1/PD-L1 antibody may be formulated as it is currently sold, but any suitable means of formulation may be employed.
  • a pharmaceutical composition comprises at least one adjuvant, pharmaceutically acceptable carrier, preservative and/or excipient. In some embodiments, a pharmaceutical composition comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight different polypeptides and at least one adjuvant, pharmaceutically acceptable carrier, preservative and/or excipient. In some embodiments, a pharmaceutical composition comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight different encoding polynucleotides of the invention and at least one adjuvant, pharmaceutically acceptable carrier, preservative and/or excipient.
  • the carrier, preservative and excipient must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to a subject to which the composition is administered. Typically, all components and the final composition are sterile and pyrogen free.
  • the composition may be a pharmaceutical composition.
  • the composition may comprise an adjuvant.
  • Adjuvants are any substance whose admixture into the composition increases or otherwise modifies the immune response elicited by the composition.
  • Adjuvants broadly defined, are substances which promote immune responses. Adjuvants may also have a depot effect, in that they also result in a slow and sustained release of an active agent from the administration site. A general discussion of adjuvants is provided in Goding, Monoclonal Antibodies: Principles & Practice (2nd edition, 1986) at pages 61-63.
  • Adjuvants may be selected from the group consisting of: A1K(SO4)2, AlNa(SO4)2, A1NH4 (SO4), silica, alum, Al(0H)3, Ca3 (PO4)2, kaolin, carbon, aluminum hydroxide, muramyl dipeptides, N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr-DMP), N-acetyl- nornuramyl-L-alanyl-D-isoglutamine (CGP 11687, also referred to as nor-MDP), N- acetylmuramyul-L-alanyl-D-isoglutaminyl-L-alanine-2-(l ’2’-dipalmitoyl-sn -glycero-3- hydroxphosphoryloxy)-ethylamine (CGP 19835 A, also referred to as MTP-PE), RIBI (MPL+TDM+CWS)
  • lipid A lipid A
  • FCA Freund’s Complete Adjuvant
  • FCA Freund's Incomplete Adjuvant
  • Merck Adjuvant 65 polynucleotides (for example, poly IC and poly AU acids), wax D from Mycobacterium, tuberculosis, substances found in Corynebacterium parvum, Bordetella pertussis, and members of the genus Brucella, Titermax, ISCOMS, Quil A, ALUN (see 5,554,372), Lipid A derivatives, choleratoxin derivatives, HSP derivatives, LPS derivatives, synthetic peptide matrixes or GMDP, Interleukin 1, Interleukin 2, Montanide ISA-51 and QS-21.
  • GM-CSF Granulocyte -macrophage colony stimulating factor
  • Adjuvants to be used with the invention in embodiments for stimulate a T cell response include oil/surfactant based adjuvants such as Montanide adjuvants (available from Seppic, Belgium), for example, Montanide ISA-51.
  • Other adjuvants are bacterial DNA based adjuvants, such as adjuvants including CpG oligonucleotide sequences.
  • Yet other adjuvants are viral dsRNA based adjuvants, such as poly I:C. GM-CSF and Imidazoquinolines are also examples of adjuvants.
  • the adjuvant is a Montanide ISA adjuvant.
  • the Montanide ISA adjuvant is Montanide ISA 51 or Montanide ISA 720.
  • a polypeptide of the invention may be therefore coupled to a carrier.
  • a carrier may be present independently of an adjuvant.
  • the function of a carrier can be, for example, to increase the molecular weight of a polypeptide fragment in order to increase activity or immunogenicity, to confer stability, to increase the biological activity, or to increase serum half-life.
  • a carrier may aid in presenting the polypeptide or fragment thereof to T-cells.
  • the polypeptide may be associated with a carrier such as those set out below.
  • the carrier may be any suitable carrier known to a person skilled in the art, for example a protein or an antigen presenting cell, such as a dendritic cell (DC).
  • Carrier proteins include keyhole limpet hemocyanin, serum proteins such as transferrin, bovine serum albumin, human serum albumin, thyroglobulin or ovalbumin, immunoglobulins, or hormones, such as insulin or palmitic acid.
  • the carrier protein may be tetanus toxoid or diphtheria toxoid.
  • the carrier may be a dextran such as sepharose. The carrier must be physiologically acceptable to humans and safe.
  • composition comprises an excipient
  • it must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering substances and the like, may be present in the excipient.
  • excipients and auxiliary substances are generally pharmaceutical agents that do not induce an immune response in the individual receiving the composition, and which may be administered without undue toxicity.
  • Pharmaceutically acceptable excipients include, but are not limited to, liquids such as water, saline, polyethyleneglycol, hyaluronic acid, glycerol and ethanol.
  • Pharmaceutically acceptable salts can also be included therein, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like
  • organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • compositions can be carried out using standard pharmaceutical formulation chemistries and methodologies all of which are readily available to the reasonably skilled artisan.
  • Such compositions may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration.
  • injectable compositions may be prepared, packaged, or sold in unit dosage form, such as in ampoules or in multi-dose containers. Some ampoules or multi-dose containers may contain a preservative.
  • Compositions include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations.
  • the active ingredient is provided in dry (for e.g., a powder or granules) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to administration of the reconstituted composition.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the composition may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution.
  • This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the adjuvants, excipients and auxiliary substances described herein.
  • Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1,3-butane diol, for example.
  • a non-toxic parenterally-acceptable diluent or solvent such as water or 1,3-butane diol, for example.
  • Other acceptable diluents and solvents include, but are not limited to, Ringer’s solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono-or di-glycerides.
  • Other compositions which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer systems.
  • compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.
  • the active ingredients of the composition may be encapsulated, adsorbed to, or associated with, particulate carriers.
  • suitable particulate carriers include those derived from polymethyl methacrylate polymers, as well as PLG microparticles derived from poly(lactides) and poly(lactide-co-glycolides). See, e.g., Jeffery et al. (1993) Pharm. Res. 10:362-368.
  • Other particulate systems and polymers can also be used, for example, polymers such as polylysine, polyarginine, polyomithine, spermine, spermidine, as well as conjugates of these molecules.
  • compositions and methods for improving the use ofPD-l/PD-Ll antibody Compositions and methods for improving the use ofPD-l/PD-Ll antibody
  • the present invention provides PD-1/PD-L1 antibody for use in a method of treating a cancer in a patient, wherein the method comprises administering PD-1/PD-L1 antibody to said patient and wherein the patient has been previously identified as having TGFbeta-1 T cell response.
  • the present invention provides PD-1/PD-L1 antibody for use in a method of treating a cancer in a patient, wherein the method comprising administering PD-1/PD-L1 antibody to said patient and wherein the value of any baseline TGFbeta-1 specific T cell response in the patient has been measured and determined to be the same or greater than a threshold value.
  • the threshold value may be the median response value. In another embodiment, the threshold value may be 75th percentile for patients with the same cancer.
  • Various threshold values are discussed elsewhere herein and may be employed. By the same cancer is meant if, for instance the invention is applied to pancreatic cancer, the median value is that for pancreatic cancer patients in general.
  • the patient may have already been, will be, or is also being treated with a CTLA-4 antibody and/or radiotherapy.
  • the CTLA-4 antibody is Ipilimumab.
  • the method of treatment may therefore further comprise administration of CTLA-4 (e.g. Ipilimumab) and/or radiotherapy.
  • the present invention also provides a CTLA-4 antibody (e.g., Ipilimumab) for use in a method of treating cancer, wherein the patient is administered with PD-1/PD-L1 antibody and/or radiotherapy, wherein the patient has been previously identified as having a TGFbeta-specific T cell response or has been identified as having a TGFbeta-specific T cell response equal or more than a threshold value.
  • the measurement for a TGFbeta-specific T cell response may have already been performed. Alternatively, it may be that such measurement forms part of the method referred to itself.
  • the present invention further provides a method of stratifying a patient with cancer into one of at least two treatment groups, the method comprising: (i) performing an assay on a sample previously obtained from the patient to detect the presence or absence of a TGFbeta-specific T cell response; (ii) allocating the patient to a first treatment group if a TGFbeta-specific response is present or allocating the patient into a second treatment group if TGFbeta-specific response is absent. In some embodiments, if the patient is allocated to the first treatment group they are to be administered with a PD-1/PD-L1 antibody.
  • the patient if the patient is allocated to the second treatment group, they are to be administered with a TGFbeta-1 peptide to increase, or bring about, a TGFbeta-1 -specific T cell response.
  • the patients allocated to the second treatment group are to be administered with a PD-1/PD-L1 antibody simultaneously, separately, or sequentially with a TGFbeta-1 peptide.
  • the present invention further provides a method of stratifying a patient into one of at least two treatment groups, the method comprising: (i) performing an assay on a sample previously obtained from the patient to detect the level of a TGFbeta-specific T cell response, if present; (ii) allocating the patient to a first treatment group if the TGFbeta-specific T cell response is at least a threshold value or allocating the patient into a second treatment group if a TGFbeta-specific response is below the threshold value.
  • the patient if the patient is allocated to the first treatment group they are to be administered with a PD-l/PD- L1 antibody.
  • the patient if the patient is allocated to the second treatment group, they are to be administered with a TGF-betal peptide to increase, or bring about, a TGFbeta- specific T cell response.
  • the patients allocated to the second treatment group are to be administered with a PD-1/PD-L1 antibody simultaneously, separately, or sequentially with a TGFbetal peptide.
  • threshold values discussed herein may be, for instance, used as the dividing line for stratification.
  • the value for the TGFbeta-specific T cell response seen for a given subject may be used to give the patient an indication of how successful treatment with PD-1/PD-L1 antibody is likely to be.
  • the present invention provides a method of providing a patient with an indication of how effective treatment with PD-1/PD-L1 antibody is likely to be for that specific patient comprising detecting in a sample from the patient the presence or absence of a TGFbeta-specific T cell response and, if present, the strength of the TGFbeta- specific T cell response, and then determining the likelihood of efficacy of PD-1/PD-L1 antibody for that subject from that measurement.
  • Such a method may comprise working out where the response falls in percentile terms.
  • It may comprise determining the magnitude of the response, if present, compared to the median value expected. Such a method, for example, may be used to determine a treatment plan. It may be used to decide on whether to stimulate a TGFbeta-specific T cell response as described herein.
  • the present invention also provides an immunogenic fragment of human TGFbeta for use in a method of treating cancer, wherein the method comprises administering the immunogenic fragment of human TGFbeta to a cancer patient that has previously been identified as lacking a TGFbeta-specific T cell response or have a TGFbeta-specific T cell response less than a threshold value, wherein the patient is also administered with a PD- 1/PD-L1 antibody.
  • immunogenic fragment of human TGFbeta is a TGFbeta- 1 peptide.
  • the method may comprise first administering the TGFbeta- 1 peptide before administering PD-1/PD-L1 antibody.
  • the method may comprise checking that a TGFbeta-specific T cell response has resulted from administering the peptide or that the response is at least a threshold value and if that has occurred then administering the PD-1/PD-L1 antibody.
  • the present invention further provides PD-1/PD-L1 antibody for use in such methods.
  • a CTLA-4 antibody e.g. Ipilimumab
  • radiotherapy is provided for use in such methods.
  • the present invention also provides use of an immunogenic TGFbeta- 1 peptide for improving cancer treatment with PD-1/PD-L1 antibody.
  • Any of the methods set out herein may be used to improve PD-1/PD-L1 antibody.
  • the improvement may be in terms of increasing overall survival time (OS). Additionally or alternatively the improvement may be in terms of increasing the length of Progression Free Survival (PFS).
  • PFS Progression Free Survival
  • the treatment increases the chance of the patient showing clinical benefit from the treatment for six or more months from the start of the treatment given.
  • TGFbeta- 1 peptide may be administered to stimulate or boost a response.
  • TGFbeta-1 peptide may be administered repeatedly. For instance, it may be administered one to five times, such as two, three, four or five times. It may be administered repeatedly until a response is seen or rises to the desired level.
  • the present invention also provides the method itself.
  • the present invention also provides use of what is set out in the manufacture of a medicament to treat the stated condition.
  • the sequence for the specific peptide TGFp-15 is: REAVPEPVLLSRAELRLLRL (SEQ ID NO: 28).
  • the peptide was acquired at a high purity (>90%) from Schafer (Copenhagen, Denmark) and was dissolved in DMSO at a concentration of 10 mM.
  • PBMCs Peripheral blood mononuclear cells
  • the normalized mean spots were defined as the mean number of spots in peptide-stimulated wells subtracted by the mean number of spots in negative control wells.
  • the in vitro cultures received 2 pl of 10 mM TGFp-15 on day 0 and then at day 1 they received 120 U/mL of IL-2 (Novartis, Switzerland). That was repeated every 7 days once or twice and after the final stimulation incubation was continued for 9-10 days after which they were set up in ELISPOT assays as described above.
  • PBMC peripheral blood mononuclear cell
  • TGFb-15 -specific immune response is important in the clinical response to SBRT/ICI treatment in patients with pancreatic cancer.
  • inducing a TGFb-15 response with therapeutic peptide vaccines might be effective, when combined with SRBT/ICI.
  • TGFb-15 specific immune response could be enhanced in PBMCs from healthy individuals and patients with pancreatic cancer by repeatedly stimulating with the epitope.
  • TGFbeta-specific anti-regulatory T cells played a role in the response to ICI therapy in pancreatic cancer.
  • pancreatic cancer approximately 95% of patients harbor an activating mutation in the KRAS-gene (Prior, I. A., et al, Cancer Res. ’ll, 2457-2467 (2012). These mutations induce the production of TGFb in transformed cells (Zdanov, S. et al., Cancer Immunol. Res. 4, 354-365 (2016) and Cheng, H. et al., Cancer Lett. 446, 103-111 (2019)).
  • TGFbeta-specific T cells would act directly on the transformed cells.
  • several other prevalent immunosuppressive cells would also be targeted.
  • Pancreatic cancer is characterized by a highly desmplastic stroma and cancer associated fibroblasts (CAFs) are the main culprits behind this feature (Kalluri, R., Nat. Rev. Cancer 16, 582-598 (2016) and Kobayashi, H. et al., Nat. Rev. Gastroenterol. Hepatol. 16, 282-295 (2019)).
  • CAFs are thought to originate from both bone marrow-derived mesenchymal stem cells and pancreatic stellate cells (Moir, J. A. G., et al. Surg. Oncol. 24, 232-238 (2015)).
  • pancreatic cancer-derived cell lines can activate CAF, which increases the deposition of extracellular matrix proteins and enhances fibrosis (Lohr, M. et al, Cancer Res. 61, 550-555 (2001) and Principe, D. R. et al. Cancer Res. 76, 2525 (2016)). Furthermore, activated CAFs also secrete TGFb, which acts in an autocrine fashion thus resulting in additional secretion of TGFb and notably intratumoral TGFb expression was shown to correlate with tissue fibrosis. Another study demonstrated that pancreatic cancer patients with high levels of fibrosis in combination with the CAF- marker aSMA, showed inferior survival (Sadozai, H.
  • the composition of immune cells in pancreatic cancer is heterogeneous (Steele, N. G. et al.,. Nat. cancer 1, 1097 (2020)) but generally, most are of myeloid origin (Steele, N. G. et al.,. Nat. cancer 1, 1097 (2020); Vayrynen, S. A. et al., Clin. Cancer Res. 27, 1069-1081 (2021); and Elyada, E. et al., Cancer Discov. 9, 1102-1123 (2019)).
  • myeloid cells include TAMs (Tumor Associated Macrophages), MDSCs (Myeloid-derived suppressor cells), and neutrophils, all expressing TGFp, which modulates the TME (tumor microenvironment).
  • TGFb is an attractive target for enhancing the effect of cancer immune therapy in pancreatic cancer.
  • TGFb TGFbeta-specific T cells that migrate to the TME; these cells will attack TGFbeta-expressing cells and release Thl cytokines; thus, TGFb signaling will be reduced, and the TME will be converted to an immunopermissive environment that favors the killing of transformed cells by tumor-specific T-cells.
  • PBMC samples from patients with pancreatic cancer treated with ICI and SBRT displayed immune responses to the TGFb-15 epitope.
  • Patients with clinical benefit from treatment had stronger TGFb- 15 -specific T-cell responses than patients with progressive disease.
  • a strong TGFb-15-specific T cell response before treatment initiation was independently associated with prolonged progression free survival and overall survival.
  • low-level TGFb-15-specific responses observed in some patients was not due to a general dysfunction of the immune system, as these patients retained a normal T- cell response to common pathogen-derived epitopes.
  • TGFb- 15-specific immune responses could be induced/ enhanced by repeated antigen stimulations. Consequently, administering therapeutic cancer vaccinations to deliver repeated TGFb- 15- antigen stimulations in patients may induce a specific T-cell response that is likely to lead to a clinical response.
  • TGFb-33 FCLGPCPYIWSLDTQYSKVL (SEQ ID NO: 55). Results
  • T-cell responses specific to TGFb-33 were independently associated with improved survival.
  • patients were stratified based on whether they showed responses above or below to or equal to the median normalized TGFb-33-specific immune response at baseline.
  • TGFb-33-specific responses were analyzed in the samples from the patients, finding that T cells isolated both at baseline and after four series of treatment displayed responses to TGFb-33 (Figure 12).
  • NLR Neutrophil-to-lymhocyte ratio
  • Non-immunogenicity of pancreatic cancer with high prevalence of immunosuppressive cells and typically a scarcity of tumor-infiltrating effector lymphocytes is considered as one of the reasons for lacking responsiveness to single-agent immunotherapies.
  • the combination of checkpoint blocking antibodies with immunomodulation of the tumor microenvironment could lead to better responses in tumor historically resistant to radiation and checkpoint blocking antibody approaches as single modalities.
  • 3-15 immune response is corelated to clinical benefit, supporting the rationale for combining of TGF
  • SBRT of 15 Gy in combination with nivolumab and ipilimumab
  • an interventional Phase I study CheckVAC NCT05721846 is being carried out to evaluate the safety and tolerability of nivolumab with ipilimumab combined with TGF
  • the study will measure adverse events, overall response rate, overall survival, progression free survival, duration of response, best overall response and disease control rate.
  • Prior therapy requirements o There is no upper limit on the number of prior chemotherapy regimens received. Participants must have received and progressed during or after at least 1 line of systemic chemotherapy in the metastatic setting (gemcitabine or 5-FU based regimens). o Notes:
  • the adjuvant/neoadjuvant treatment will be considered as 1 line of systemic treatment.
  • discontinuation of 1 drug in a multi-drug regimen and continuation of other drug(s), is considered part of the same line of treatment.
  • Restarting the same regimen after a drug holiday or maintenance chemotherapy can also be considered part of the same line of treatment.
  • Switching from IV (5-FU) to an oral formulation (capecitabine) of the same drug is also considered part of the same line of treatment
  • Minimum time from first systemic therapy for recurrent/metastatic adenocarcinoma of pancreas to progression should be at least 3 months
  • a highly effective method(s) of contraception (failure rate of less than 1% per year) is required.
  • the individual methods of contraception and duration should be determined in consultation with the investigator.
  • WOCBP must follow instructions for birth control when the half-life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 30 days plus the time required for the investigational drug to undergo five half-lives.
  • the half-life of nivolumab and ipilimumab is up to 25 days and 18 days, respectively. WOCBP should therefore use an adequate method to avoid pregnancy during the treatment and for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug
  • Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. The investigator shall review contraception methods and the time period that contraception must be followed. Men that are sexually active with WOCBP must follow instructions for birth control when the halflife of the investigational drug is greater than 24 hours, contraception should be continued for a period of 90 days plus the time required for the investigational drug to undergo five half-lives. The half-life of nivolumab is up to 25 days. Men who are sexually active with WOCBP must continue contraception during the treatment and for 31 weeks (90 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. Women who are not of childbearing potential (i.e. who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • TGFb-15 peptide vaccine will enhance the clinical benefit of SBRT, nivolumab and ipilimumab for the treatment of refractory PC.

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Abstract

La présente invention concerne l'amélioration du traitement du cancer avec l'anticorps PD-1/PD-L1. En particulier, l'invention est basée sur la découverte selon laquelle des patients ayant une réponse de cellule T spécifique du TGFβ sont plus susceptibles de présenter un résultat positif dans le traitement du cancer avec l'anticorps PD-1/PD-L1. Par conséquent, l'invention concerne le traitement de ce groupe de patients avec l'anticorps PD-1/PD-L1 ainsi que la promotion active d'une réponse de cellule T spécifique du TGFβ pour améliorer le traitement avec l'anticorps PD-1/PD-L1.
PCT/EP2023/080070 2022-10-28 2023-10-27 Thérapie WO2024089244A2 (fr)

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