TGF-BETA INHIBITORS FOR USE FOR TREATING RESISTANT OR UNRESPONSIVE CANCER IN PATIENTS
The present disclosure provides TGFβ inhibitor therapy for treating immunosuppressive conditions, such as cancer, either as a monotherapy or combination/adjunct therapy. Selection of suitable therapy and patients who are likely to benefit from such therapy are also disclosed, as well as methods of treating cancer and methods of predicting and monitoring therapeutic response. Related compositions, methods and therapeutic use are also disclosed.
1 . A TGFβ1 inhibitor for use in the treatment of cancer in a patient who has received prior therapy for the cancer, wherein the treatment comprises administering the TGFβ1 inhibitor in an amount sufficient to inhibit the growth of a solid tumor or reduce the volume of a solid tumor, wherein the cancer is renal cell carcinoma (RCC), head and neck squamous cell carcinoma (HNSCC), ovarian cancer, melanoma, testicular cancer, colorectal cancer, pancreatic cancer, squamous cell skin carcinoma, triple-negative breast cancer (TNBC), or liver cancer.
2 . The TGFβ1 inhibitor for use according to claim 1 , wherein the prior cancer therapy comprises checkpoint inhibitor therapy, chemotherapy, and/or radiation therapy.
3 . The TGFβ1 inhibitor for use according to claim 1 or 2 , wherein the prior cancer therapy comprises anti-PD-(L)1 (e.g., pembrolizumab, nivolumab, cemiplimab, atezolizumab, dostarlimab, durvalumab, avelumab), anti-CTLA4 (e.g., ipilimumab, tremelimumab), tyrosine kinase inhibitors (e.g., sunitinib, cabozantinib, imatinib, gefitinib, sorafenib, erlotinib, lapatinib, canertinib, semaxinib, vatalanib, leflunomide, etc.), phosphoinositide 3-kinase (PI3K) inhibitors, paclitaxel, carboplatin, topotecan, doxil, gemcitabine, altretamine, bevacizumab, letrozole, carboplatin/taxol, leuprorelin, carboplatin/docetaxel, and/or bevacizumab.
4 . The TGFβ1 inhibitor for use according to any one of claims 1-3 , wherein the patient has received multiple lines of prior cancer therapies aimed to treat the cancer.
5 . The TGFβ1 inhibitor for use according to any one of claims 1-4 , wherein the cancer was resistant or unresponsive to the prior cancer therapies.
6 . The TGFβ1 inhibitor for use according to any one of claims 1-5 , wherein the disease progressed during the prior therapies.
7 . The TGFβ1 inhibitor for use according to any one of claims 1-6 , wherein the patient experienced adverse events in response to the prior cancer therapies, leading to the discontinuation of the therapy or therapies.
8 . The TGFβ1 inhibitor for use according to any one of claims 1-7 , wherein the cancer is from RCC, HNSCC, ovarian carcinoma, TNBC, pancreatic adenocarcinoma, colorectal carcinoma, or squamous cell skin carcinoma.
9 . The TGFβ1 inhibitor for use according to any one of claims 1-8 , wherein the patient has a metastasis (i.e., a primary cancer has metastasized) at screening (prior to initiating the treatment of the TGFβ1 inhibitor), wherein optionally, the cancer has metastasized to multiple sites.
10 . The TGFβ1 inhibitor for use according to any one of claims 1-9 , wherein a therapeutically effective amount of the TGFβ1 inhibitor is administered to the patient, wherein optionally, the therapeutically effective amount is:
(i) an amount that achieves a stable disease (SD), e.g., no disease progression for 16 weeks or longer (e.g., 6 months, 7 months, 8 months, 9 months, 10 months, or longer) upon/during the treatment;
(ii) an amount that achieves a partial response (PR), e.g., 30% or greater tumor reduction. In some embodiments, tumor reduction is measured by percent change in sum of diameters (SOD) in target lesions from baseline, wherein further optionally, the therapeutically effective amount achieves 50% or greater reduction in SOD from baseline.
11 . The TGFβ1 inhibitor for use according to any one of claims 1-10 , wherein the TGFβ1 inhibitor comprises an agent aimed to reduce and capable of reducing the TGFβ1 signaling pathway, wherein optionally the agent is selected from:
(i) inhibitors of TGFβ1 activators, such as integrins that bind the RGD motif within the LAP domain of latent TGFβ1;
(ii) inhibitors of TGFβ1 activation, such as antibodies that bind latent TGFβ1 thereby inhibiting the release of the growth factor from the latent complex;
(iii) inhibitors of the mature (soluble) TGFβ1 ligand, such as neutralizing antibodies, ligand traps that incorporate ligand-binding modules of the TGFβ receptor(s), and nucleic acid-based inhibitors, e.g., siRNA and antisense oligonucleotides; and,
(iv) TGFβ receptor antagonists, such as Alk5 inhibitors.
12 . The TGFβ1 inhibitor for use according to any one of claims 1-11 , wherein the TGFβ1 inhibitor preferentially inhibits TGFβ1 over TGFβ2 and/or TGFβ3.
13 . The TGFβ1 inhibitor for use according to any one of claims 1-11 , wherein the TGFβ1 inhibitor preferentially inhibits TGFβ1 and TGFβ2 over TGFβ3.
14 . The TGFβ1 inhibitor for use according to any one of claims 1-11 , wherein TGFβ1 inhibitor is a TGFβ1-selective inhibitor, wherein optionally the TGFβ1-selective inhibitor is SRK-181.
15 . The TGFβ1 inhibitor for use according to any one of claims 1-11 , wherein the TGFβ1 inhibitor is or comprises: SRK-181 (by Scholar Rock), RG6440 (SOF10) (by Roche/Chugai), ABBV-151 (livmoniplimab) (by AbbVie), NIS793 (XOMA-089) (by Novartis), PLN-10195 (by Pliant), ES014 (by Elpiscience), Cotsiranib (STP705) (by Sirnaomics), Bintrafusp alpha (M7824), Dalutrafusp alpha (AGEN14423), BMS-986416 (AVID200), MK-2225 (by MERCK), PM8001 (by Biotheus), Vactosertib (by Medpacto), BCA101 (by Bicara), TU2218 (NCE401) (by TiUM), ATB-301 (by Autotelic Bio/Clinigen), AdAPT-001 (AIM-001) (by EpicentRx), CART-PSMA-TGF-bRDN (by Tmunity Therapeutics), HCW9218 (by HCW Biologics), SH3051 (by Sanhome), TST005 (by Transcenta), GS19 (GT90008) (by Kintor (Gensun)), BJ-005 (by BJ Bioscience), QLS31901 (by Qilu Pharmaceutical), TQB2858 (by Chia Tal-tianqing), Y101D (by YZY Biopharma), Charis 1000 (C1K) (by Ensol Biosciences), and/or Fresolimumab (GC1008).
16 . The TGFβ1 inhibitor for use according to any one of claims 1-15 , wherein the TGFβ1 inhibitor is selected from the antibodies and antigen-binding fragments thereof disclosed in the following publications, as well as those that compete or cross-compete for antigen binding (e.g., sharing overlapping epitopes) with such antibodies: WO 2020/104460, WO 2020/014473, WO 2019/163927, WO 2021/039945, WO 2015/015003, WO 2018/013939, WO 2021/142427, WO 2016/161410, WO 2019/075090, and WO 2020/160291.
17 . A TGFβ1-selective inhibitor for use in the treatment of ovarian cancer in a patient, wherein the TGFβ1-selective inhibitor is an antibody that binds a latent TGFβ1 complex thereby inhibiting its activation, wherein the treatment comprises administration of the TGFβ1-selective inhibitor so as to achieve stable disease (SD) for 6 months or longer, wherein optionally the TGFβ1-selective inhibitor is SRK-181 dosed as monotherapy at 240-2400 mg Q3W or Q2W, and wherein the patient received prior cancer therapy, wherein further optionally the prior cancer therapy comprises Paclitaxel/Carboplatin, Topotecan, Doxil, Gemcitabine, Altretamine, Bevacizumab/Gemcitabine/Carboplatin, Letrozole, Carboplatin/Taxol, Leuprorelin, Carboplatin/Docetaxel, Carboplatin/Docetaxel/Bevacizumab, or any combinations thereof.
18 . A TGFβ1-selective inhibitor for use in the treatment of RCC, HNSCC, melanoma, or squamous cell skin carcinoma, in a patient whose disease progressed in prior anti-PD-(L)1 therapy, wherein the TGFβ1-selective inhibitor is an antibody that binds a latent TGFβ1 complex thereby inhibiting its activation, wherein the treatment comprises administration of the TGFβ1-selective inhibitor in combination with an anti-PD-(L)1 therapy, wherein optionally the TGFβ1-selective inhibitor is SRK-181 dosed at 240-2400 mg Q3W or Q2W (e.g., 1500 mg Q3W or 1000 mg Q2W).
19 . The TGFβ1 inhibitor for use according to any of one of claims 1-18 , wherein the cancer comprises a solid tumor, wherein the solid tumor is a CD8+ T cell-infiltrated tumor.
20 . The TGFβ1 inhibitor for use according to any one fo claim 1-19 , wherein a tumor microenvironment (TME) of the CD8+ T cell-infiltrated tumor has a high Treg/CD8+ T cell ratio prior to the treatment.
21 . The TGFβ1 inhibitor for use according to any one fo claim 1-20 , wherein CD8+ T cells in the TME express low levels of a proinflammatory cytokine and/or a cytotoxic enzyme prior to the treatment.
22 . The TGFβ1 inhibitor for use according to claim 21 , wherein the proinflammatory cytokine comprises IFNγ and the cytotoxic enzyme comprises perforin and granzyme A/B.
23 . The TGFβ1 inhibitor for use according to any one of claims 1-22 , wherein the patient has elevated levels of circulating MDSCs, preferably gMDSCs, prior to treatment.
24 . The TGFβ1 inhibitor for use according to any of one of claims 1-23 , wherein the patient has an elevated number of platelets in the cancer prior to the treatment.
25 . The TGFβ1 inhibitor for use according to any of one of claims 1-24 , wherein TGFβ1 is over-expressed in the cancer prior to the treatment.
26 . The TGFβ1 inhibitor for use according to any of one of claims 1-25 , wherein an TGFβ1 activator is detected at an increased level in the cancer prior to the treatment.
27 . The TGFβ1 inhibitor for use according to claim 26 , wherein the TGFβ1 activator comprises an integrin capable of binding an RGD motif and comprising alpha-v, alpha-5, alpha-11, beta-6, and/or beta-8.
28 . The TGFβ1 inhibitor for use according to claim 26 , where the TGFβ1 activator comprises kallikrein, chemotrypsin, trypsin, elastase, plasmin, thrombin, zinc metalloprotease (MMP), and/or ADAM protease.
29 . The TGFβ1 inhibitor for use according to any of one of claims 1-28 , wherein an increase in a ROS marker is present and/or is expected to be present in the patient prior to and/or during the treatment, wherein the ROS marker comprises isoprostanes (IsoPs), malondialdehyde (MDA), nitrotyrosine, S-glutathionylation, myeloperoxidase (MPO), oxidized low-density lipoprotein (OxLDL), and/or antioxidant enzymes.
30 . The TGFβ1 inhibitor for use according to any of one of claims 1-29 , wherein an increased deposition of extracellular matrix (ECM) is detected in the cancer prior to the treatment, wherein the increased deposition of ECM is indicated by the level of an ECM marker comprising collagen, fibronectin, and/or fibrillin and/or by the level of a cancer-associated fibroblast (CAF) marker comprising actin alpha, platelet-derived growth factor receptor alpha (PDGFRα/CD140a), platelet-derived growth factor receptor beta (PDGFRβ/CD140b), fibroblast specific protein 1 (FSP-1/S100A4), fibroblast activation protein (FAP), and/or nicotinamide N-methyltransferase (NNMT).
31 . The TGFβ1 inhibitor for use according to any of one of claims 1-30 , wherein a decreased level of an epithelial marker and/or an increased level of a mesenchymal marker is detected in the cancer prior to the treatment, wherein the epithelial marker comprises E-cadherin, α-catenin, γ-catenin, and/or cytokeratin and the mesenchymal marker comprises fibronectin, vimentin, and/or N-cadherin.
32 . The TGFβ1 inhibitor for use according to any of one of claims 1-31 , wherein an immunosuppression marker is detected in the cancer prior to the treatment wherein the immunosuppression marker comprises a Treg marker and/or LRRC33, and the Treg marker comprises CD4, FOXP3, and/or CD25.
33 . The TGFβ1 inhibitor for use according to any of one of claims 1-32 , wherein the cancer is SMAD4-deficient.
34 . The TGFβ1 inhibitor for use according to any of one of claims 1-33 , wherein the cancer is methylthioadenosine phosphorylase (MTAP)-deficient.
35 . The TGFβ1 inhibitor for use according to claim 34 , wherein
(A) the cancer has a deletion in the 9p21 locus, and optionally further contains an additional deletion of a tumor suppressor gene;
(B) the cancer has reduced expression of MTAP; and/or
(C) a mutant MTAP with decreased activity is produced in the cancer.
36 . The TGFβ1 inhibitor for use according to any of one of claims 1-35 , wherein a low level of interferon gamma (IFNγ) is detected in the cancer prior to the treatment.
37 . The TGFβ1 inhibitor for use according to any of one of claims 1-36 , wherein the treatment comprises
(i) measuring a biomarker in the patient,
(ii) administering the TGFβ1 inhibitor in an amount sufficient to inhibit the growth of a solid tumor or reduce the volume of a solid tumor to the patient,
(iii) measuring the biomarker after administration of the TGFβ1 inhibitor; and
(iv) continuing to administer the treatment if a change in the biomarker is detected.
38 . The TGFβ1 inhibitor for use according to claim 37 , wherein the biomarker comprises
(A) a TGFβ1 transcript and/or a TGFβ1 protein,
(B) an integrin capable of binding an RGD motif and comprising alpha-v, alpha-5, alpha-11, beta-6, and/or beta-8,
(C) a protease capable of activating TGFβ1,
(D) a ROS marker,
(E) an ECM marker,
(F) a CAF marker,
(G) an epithelial marker,
(H) a mesenchymal marker,
(I) an immunosuppression marker,
(J) a SMAD4 gene, a SMAD4 transcript, and/or a SMAD4 protein,
(K) an MTAP gene, an MTAP transcript, and/or an MTAP protein,
(L) IFNγ,
(M) circulating MDSCs,
(N) platelets,
(O) a heightened Treg/CD8+ T cell ratio in the CD8+ T cell-infiltrated solid tumor, and/or
(P) CD8+ T cells expressing low levels of a proinflammatory cytokine and/or a cytotoxic enzyme in the CD8+ T cell-infiltrated solid tumor.
39 . The TGFβ1 inhibitor for use according to claim 37 , wherein the step (iii) of the treatment comprises detecting in the cancer a deletion in the 9p21 locus and optimally further detecting an additional deletion in a tumor suppressor gene.
40 . A TGFβ1 inhibitor for use in the treatment of cancer in a patient, wherein the treatment comprises
(i) administering the TGFβ1 inhibitor in an amount sufficient to inhibit the growth of a solid tumor or reduce the volume of a solid tumor; and
(ii) administering a genotoxic therapy before and/or concurrently with administration of the TGFβ1 inhibitor, or administering a genotoxic therapy concurrently with and/or after administration of the TGFβ1 inhibitor.
41 . The TGFβ1 inhibitor for use according to claim 40 , wherein the genotoxic therapy administration starts at least one hour after the initiation of the TGFβ1 inhibitor administration.
42 . The TGFβ1 inhibitor for use according to claim 40 , wherein the genotoxic therapy administration starts at least one day after the initiation of the TGFβ1 inhibitor administration.
43 . The TGFβ1 inhibitor for use according to claim 40 , wherein the genotoxic therapy administration starts at least one week after the initiation of the TGFβ1 inhibitor administration.
44 . The TGFβ1 inhibitor for use according to any one of claims 40-43 , wherein the treatment further comprises continuing to administer the TGFβ1 inhibitor after the genotoxic therapy ends.
45 . The TGFβ1 inhibitor for use according to any one of claims 40-44 , wherein the genotoxic therapy is a chemotherapy and/or a radiation therapy.
46 . The TGFβ1 inhibitor for use according to any one of claims 40-45 , wherein the chemotherapy comprises administration of 5-FU, paclitaxel, cisplatin, and/or bleomycin to the patient.
47 . The TGFβ1 inhibitor for use according to any one of claims 40-46 , wherein the patient further receives a checkpoint inhibitor therapy.
48 . The TGFβ1 inhibitor for use according to any one of claims 40-47 , wherein the patient has received a checkpoint inhibitor therapy, chemotherapy, and/or radiation therapy of the cancer prior to receiving the TGFβ1 inhibitor.
49 . The TGFβ1 inhibitor for use according to any one of claims 40-48 , wherein the TGFβ1 inhibitor is a TGFβ1-selective inhibitor, and optionally the TGFβ1-selective inhibitor is SRK-181.
50 . The TGFβ1 inhibitor for use according to any one of claims 40-49 , wherein the cancer is RCC, HNSCC, ovarian cancer, melanoma, testicular cancer, colorectal cancer, pancreatic cancer, squamous cell skin carcinoma, TNBC, or liver cancer.
51 . The TGFβ1 inhibitor for use according to any one of claims 1-50 , wherein the cancer is ccRCC.
52 . A TGFβ1 inhibitor for use in the treatment of a cancer in a subject, wherein the treatment comprises administration of a TGFβ1 inhibitor to the subject in an amount effective to treat the cancer, wherein CD8+ T cells have infiltrated a tumor microenvironment (TME) in the cancer, and wherein the cancer is resistant or refractory to a cancer therapy, wherein optionally the cancer therapy comprises a checkpoint inhibitor and/or a genotoxic agent therapy, wherein further optionally, the genotoxic agent therapy is radiation therapy or chemotherapy.
53 . The TGFβ1 inhibitor for use according to claim 52 , wherein the TME has a high Treg/CD8+ T cell ratio prior to the treatment.
54 . The TGFβ1 inhibitor for use according to claim 52 or 53 , wherein CD8+ T cells in the TME express low levels of a proinflammatory cytokine and/or a cytotoxic enzyme prior to the treatment.
55 . The TGFβ1 inhibitor for use according to claim 54 , wherein the proinflammatory cytokine comprises IFNγ and the cytotoxic enzyme comprises perforin and granzyme A/B.
56 . The TGFβ1 inhibitor for use according to any one of claims 52-55 , wherein the patient has elevated levels of circulating MDSCs, preferably gMDSCs, prior to treatment.
57 . The TGFβ1 inhibitor for use according to any of one of claims 52-56 , wherein the patient has an elevated number of platelets in the cancer prior to the treatment.
58 . The TGFβ1 inhibitor for use according to any one of claims 52-57 , wherein the subject is further treated with a cancer therapy, selected from checkpoint inhibitors and genotoxic agent therapies.
59 . The TGFβ1 inhibitor for use according to any one of claim 52-58 , wherein the cancer is undergoing or has undergone epithelial-to-mesenchymal transition (EMT).
60 . The TGFβ1 inhibitor for use according to any one of claims 52-59 , wherein the cancer comprises a greater number of Treg cells than non-cancerous/normal tissue.
61 . The TGFβ1 inhibitor for use according to any one of claims 52-60 , wherein a biological sample collected from the subject shows elevated levels of TGFB1 and/or TGFβ1 transcripts, an integrin capable of binding an RGD motif, a protease capable of activating TGFβ1, a ROS marker, a mesenchymal marker; a CAF marker; an immunosuppression marker, Treg cells, platelets, circulating MDSCs, and/or Treg/CD8+ T cell ratio.
62 . The TGFβ1 inhibitor for use according to any one of claims 52-60 , wherein a biological sample collected from the subject shows decreased levels of epithelial markers, SMAD4 transcripts and/or proteins, methylthioadenosine phosphorylase (MTAP) transcripts and/or proteins, a proinflammatory cytokine, and/or a cytotoxic enzyme.
63 . The TGFβ1 inhibitor for use according to any one of claims 52-62 , wherein the cancer is selected from renal cell carcinoma (RCC), head and neck squamous cell carcinoma (HNSCC), ovarian cancer, melanoma, testicular cancer, colorectal cancer, pancreatic cancer, squamous cell skin carcinoma, triple-negative breast cancer (TNBC), and liver cancer.
64 . The TGFβ1 inhibitor for use according to any one of claims 52-63 , wherein the cancer is ccRCC.
65 . The TGFβ1 inhibitor for use according to any one of claims 52-64 , wherein the TGFβ1 inhibitor is SRK-181.