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Can Immunogenic Chemotherapies Relieve Cancer Cell Resistance to Immune Checkpoint Inhibitors?

ABSTRACT: The unprecedented clinical activity of checkpoint blockade in several types of cancers has formally demonstrated that anti-tumor immune responses are crucial in cancer therapy. Durable responses seen in patients treated with immune checkpoint inhibitors (ICI) show that they can trigger the establishment of long-lasting immunologic memory. This beneficial outcome is however achieved for a limited number of patients. In addition, late relapses are emerging suggesting the development of acquired resistances that compromise the anticancer efficacy of ICI. How can this be prevented through combination therapies? We here review the functions of immune checkpoints, the successes of ICI in treating cancer and their therapeutic limits. We discuss how conventional cancer therapies can be properly selected to set up combinatorial approaches with ICI leading to treatment improvement. We finally summarize clinical data showing the ongoing progress in cancer treatment involving ICI and chemotherapy combination strategies.

SUBMITTER: Rivera Vargas T

PROVIDER: S-EPMC6548803 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Can Immunogenic Chemotherapies Relieve Cancer Cell Resistance to Immune Checkpoint Inhibitors?

Rivera Vargas Thaiz T Apetoh Lionel L

Frontiers in immunology 20190529

The unprecedented clinical activity of checkpoint blockade in several types of cancers has formally demonstrated that anti-tumor immune responses are crucial in cancer therapy. Durable responses seen in patients treated with immune checkpoint inhibitors (ICI) show that they can trigger the establishment of long-lasting immunologic memory. This beneficial outcome is however achieved for a limited number of patients. In addition, late relapses are emerging suggesting the development of acquired re ...[more]

PMID: 31191545

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Project description:BackgroundResistance or even hyper-progression to immune checkpoint inhibitors (ICIs) manifesting as accelerated disease progression or death has impeded the clinical use of ICIs. The transforming growth factor beta (TGFβ) receptor pathway has been identified in contributing to immune dysfunction, which might be associated with resistance to ICIs. We aimed to explore the role of TGFβ in the resistance to ICIs in non-small cell lung cancer (NSCLC) in this study.MethodsPublic cohorts with patients treated with ICIs or chemotherapy including POPLAR/OAK (n = 853), MSKCC (n = 1662) and Van Allen (n = 57) and TCGA (n = 3210) cohorts were obtained and analyzed.ResultsThe expression of immune-checkpoint related genes, including programmed death-ligand 1 (CD274), lymphocyte-activation gene 3 (LAG3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death ligand 1 (PDCD1), and programmed cell death 1 ligand 2 (PDCD1LG2) were significantly upregulated in transforming growth factor beta TGFβ receptor 2 (TGFβR2)-mutated patients than those with wild-type TGFBR2 (p < 0.05). In the POPLAR/OAK cohort, TGFBR2-mutated patients showed shorter progression-free survival (PFS) [ p = 0.004; hazard ratio (HR), 2.83; 95% confidence interval (CI), 1.34-6.00] and overall survival (OS) ( p = 0.0006; HR, 3.46; 95% CI, 1.63-7.35) than those with wild-type TGFBR2 when treated with ICIs but not chemotherapy. In the merged MSKCC and Van Allen cohorts, a similar result was observed that the OS was inferior in patients with mutated TGFBR2 compared with those with wild-type TGFBR2 (p = 0.007; HR, 2.53; 95% CI, 1.25-5.12). The association between TGBFR2 mutation and survival remained significant in multivariable cox regression in both POPLAR/OAK cohort (p = 0.02; HR, 2.53; 95% CI, 1.17-5.45) and merged cohort (p = 0.008; HR, 2.63; 95% CI, 1.29-5.35). We further evaluated the association between TGFBR2 mutations and OS in multiple types of tumors. The association between TGFBR2 mutations and OS remained significant in NSCLC (p = 0.02; HR, 2.47; 95% CI, 1.16-5.26), but not in other type of tumors.ConclusionsWe identified that TGFBR2 mutation predicted the resistance to ICIs in NSCLCs. The clinical delivery of ICIs should be cautious in those patients.

Project description:Malignant cells have the capacity to rapidly grow exponentially and spread in part by suppressing, evading, and exploiting the host immune system. Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. In recent years, manipulation of immune checkpoints or pathways has emerged as an important and effective form of immunotherapy. Agents that target cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied and recognized. Immunotherapy, however, extends beyond immune checkpoint therapy by using new molecules such as chimeric monoclonal antibodies and antibody drug conjugates that target malignant cells and promote their destruction. Genetically modified T cells expressing chimeric antigen receptors are able to recognize specific antigens on cancer cells and subsequently activate the immune system. Native or genetically modified viruses with oncolytic activity are of great interest as, besides destroying malignant cells, they can increase anti-tumor activity in response to the release of new antigens and danger signals as a result of infection and tumor cell lysis. Vaccines are also being explored, either in the form of autologous or allogenic tumor peptide antigens, genetically modified dendritic cells that express tumor peptides, or even in the use of RNA, DNA, bacteria, or virus as vectors of specific tumor markers. Most of these agents are yet under development, but they promise to be important options to boost the host immune system to control and eliminate malignancy. In this review, we have provided detailed discussion of different forms of immunotherapy agents other than checkpoint-modifying drugs. The specific focus of this manuscript is to include first-in-human phase I and phase I/II clinical trials intended to allow the identification of those drugs that most likely will continue to develop and possibly join the immunotherapeutic arsenal in a near future.

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Can Immunogenic Chemotherapies Relieve Cancer Cell Resistance to Immune Checkpoint Inhibitors?

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Can Immunogenic Chemotherapies Relieve Cancer Cell Resistance to Immune Checkpoint Inhibitors?

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