Cancer Immune Checkpoint Research Articles

Programmed cell death protein-1/programmed cell death ligand-1 pathway inhibition and predictive biomarkers: understanding transforming growth factor-beta role.

A deeper understanding of the key role of the immune system in regulating tumor growth and progression has led to the development of a number of immunotherapies, including cancer vaccines and immune checkpoint inhibitors. Immune checkpoint inhibitors target molecular pathways involved in immunosuppression, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway, with the goal to enhance the host's own immune anticancer response. In phase I-III trials, anti-PD-1/PD-L1 antibodies have demonstrated to be effective treatment strategies by inducing significant durable tumor responses, with manageable toxicities, in patients with various malignancies, including those traditionally considered non-immunogenic, such as non-small cell lung cancer (NSCLC). Identification of predictive biomarkers to select patients for immune therapies is currently being investigated to improve their therapeutic efficacy. Transforming growth factor-β (TGF-β), a pleiotropic cytokine with immunosuppressive effects on multiple cell types of the innate and adaptive immune system, has emerged as one of the potential key factors modulating response to immune checkpoint inhibitors. However, due to the complexity of the anti-cancer immune response, the predictive value of many other factors related to cancer cells or tumor microenvironment needs to be further explored.

Immunotherapy in Prostate Cancer: Challenges and Opportunities

Although treatment options for castration-resistant prostate cancer (CRPC) have increased over the last decade, there remains a need for strategies that can provide durable disease control and long-term benefit. Recently, immunotherapy has emerged as a viable and attractive strategy for the treatment of CRPC. To date, there are multiple strategies to target the immune system, and several approaches including therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in clinical trials. With regard to this, we report the results of the most recent clinical trials investigating immunotherapy in CRPC and discuss the future development of immunotherapy for CRPC, as well as the potential importance of biomarkers in the future progress of this field.

Immune Reactivation by Cell-Free Fetal DNA in Healthy Pregnancies Re-Purposed to Target Tumors: Novel Checkpoint Inhibition in Cancer Therapeutics.

The role of the immune system in cancer progression has become increasingly evident over the past decade. Chronic inflammation in the promotion of tumorigenesis is well established, and cancer-associated tolerance/immune evasion has long been appreciated. Recent developments of immunotherapies targeting cancer-associated inflammation and immune tolerance, such as cancer vaccines, cell therapies, neutralizing antibodies, and immune checkpoint inhibitors, have shown promising clinical results. However, despite significant therapeutic advances, most patients diagnosed with metastatic cancer still succumb to their malignancy. Treatments are often toxic, and the financial burden of novel therapies is significant. Thus, new methods for utilizing similar biological systems to compare complex biological processes can give us new hypotheses for combating cancer. One such approach is comparing trophoblastic growth and regulation to tumor invasion and immune escape. Novel concepts regarding immune activation in pregnancy, especially reactivation of the immune system at labor through toll like receptor engagement by fetal derived DNA, may be applicable to cancer immunotherapy. This review summarizes mechanisms of inflammation in cancer, current immunotherapies used in the clinic, and suggestions for looking beyond oncology for novel methods to reverse cancer-associated tolerance and immunologic exhaustion utilizing mechanisms encountered in normal human pregnancy.

Abstract LB-226: Depletion of kynurenine using an engineered therapeutic enzyme potently inhibits cancer immune checkpoints both as a monotherapy and in combination with anti-PD-1

Abstract Introduction: The kynurenine pathway is of key importance for immune suppression in cancer, a function exerted primarily via kynurenine as an AhR ligand that potently impairs adaptive immune responses. Inhibition of kynurenine (Kyn) synthesis, mediated by IDO1, TDO (and possibly IDO2) is of great interest for cancer immune checkpoint inhibition, with 3-4 IDO1 inhibitors currently in clinical development. However: (1) IDO1 inhibition has marginal anti-cancer effects as a monotherapy; (2) IDO1 inhibitors only block one of the two major pathways for Kynureine synthesis (the other being via TDO) and (3) IDO1 inhibition does generally not impact the serum concentration of Kynurenine and thus no pharmacodynamic marker is available. Experimental: We postulated that administration of a therapeutic enzyme (Kynureninase) that can degrade Kyn into non-toxic and immunologically inactive metabolites (Alanine and anthranilic acid) may be able to: (a) potently relieve cancer immune suppression. An extensive protein engineering campaign was carried out to develop a Kynureninase suitable for therapeutic administration which was then PEGylated (Kynase-PEG) to enable long circulation persistence. Kynase-PEG was evaluated in the well-established B16-OVA melanoma model in wild type C57BL/6J mice as a monotherapy and in combination with anti-PD-1 administration. Quantitation of tumor size/regression, histology, as well as flow cytometric analyses assessing lymphocytes in the spleen, tumor (TILs) and tumor-draining lymph nodes (dLNs) was used to evaluate efficacy. Summary: Administration of KYNase-PEG in B16-OVA melanoma allografts in C57BL/6J mice reduced serum Kyn levels and resulted in significant tumor growth retardation and extended survival in a manner indistinguishable from that observed with immune checkpoint inhibitors anti-PD1 (clone RMP1-14) or anti-CTLA-4 (clone 9D9) antibodies. KYNase-PEG administration did not display anti-tumor activity in NOD-scid Il2Rγ-/- mice or in IDO1-/- mice revealing that the function of the enzyme is dependent on adaptive immune responses and also on the function of stromal IDO1. Consistent with the hypothesis that depletion of Kyn relieves immune inhibition, we observed a marked increase in CD8+ TILs expressing Gzm B + IFNγ, enhanced proliferation of CD4+ and CD8+ T cells in the tumor dLNs as well as changes in tumor neovascularization. Importantly, combination of KYNase-PEG and anti-PD-1 administration resulted in complete tumor eradication in 60% of the animals (n = 10 per group) for >100 days, with all the surviving animals completely rejecting tumors following re-challenge. For comparison, anti-PD-1 treatment alone, only led to 20% long-term survival in this model. Conclusions: We demonstrated that unlike IDO1 inhibitors, KYNase-PEG displays a significant anti-tumor efficacy as a monotherapy as well as excellent synergism with anti-PD1. The observed increase in tumor infiltration and proliferation of cytotoxic CD8+ T cells argues that the mechanism of action of Kynase-PEG acts by relieving the immune suppression that normally occurs in the tumor microenvironment as a consequence of Kyn accumulation. Thus, KYNase-PEG represent a “first in class” immune checkpoint enzyme. Progress in developing a clinical candidate enzyme will be discussed. Citation Format: Everett Stone, Nicholas Marshall, Moses Donkor, Kendra Triplett, John Blazek, Todd Triplett, Lauren Ehrlich, George Georgiou. Depletion of kynurenine using an engineered therapeutic enzyme potently inhibits cancer immune checkpoints both as a monotherapy and in combination with anti-PD-1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-226. doi:10.1158/1538-7445.AM2015-LB-226

The interplay of immunotherapy and chemotherapy: harnessing potential synergies.

Although cancer chemotherapy has historically been considered immune suppressive, it is now accepted that certain chemotherapies can augment tumor immunity. The recent success of immune checkpoint inhibitors has renewed interest in immunotherapies, and in combining them with chemotherapy to achieve additive or synergistic clinical activity. Two major ways that chemotherapy promotes tumor immunity are by inducing immunogenic cell death as part of its intended therapeutic effect and by disrupting strategies that tumors use to evade immune recognition. This second strategy, in particular, is dependent on the drug, its dose, and the schedule of chemotherapy administration in relation to antigen exposure or release. In this Cancer Immunology at the Crossroads article, we focus on cancer vaccines and immune checkpoint blockade as a forum for reviewing preclinical and clinical data demonstrating the interplay between immunotherapy and chemotherapy.

The therapeutic promise of disrupting the PD-1/PD-L1 immune checkpoint in cancer: unleashing the CD8 T cell mediated anti-tumor activity results in significant, unprecedented clinical efficacy in various solid tumors

The role of immune checkpoints in modulating the magnitude as well as the functional profile of T cell responses is increasingly understood in molecular detail. Antibody-mediated blockade of co-inhibitory receptors has been shown to restore T cell function in both chronic viral infections and cancer. The latter has been successfully translated to new therapeutic options in the treatment of cancer. Indeed, monoclonal antibodies blocking either CTLA-4 or PD-1 have recently been approved for the treatment of metastatic melanoma in the United States, Europe and Japan. In this commentary, we summarize and put into perspective five letters recently published back to back in the November 27 (2014) issue of Nature reporting on different immunological and clinical aspects of blockade of the PD-1/PD-L1 pathway in tumor bearing hosts. Notably, treatment with anti-PD-L1 blocking antibody was shown result in profound clinical responses in patients with several solid tumor including bladder, lung and head and neck carcinomas among others. These five simultaneous publications highlight the tremendous therapeutic potential of targeting the PD-1/PD-L1 immune checkpoint and emphasize the need to identify appropriate biomarkers to guide their optimal clinical application.

Therapeutic vaccines as a promising treatment modality against prostate cancer: rationale and recent advances.

Cancer immunotherapy was deemed the medical breakthrough of 2013, in part because it can induce a rapid, durable, self-propagating and adaptable immune response. Specifically in prostate cancer, immunotherapy has emerged as a viable and attractive treatment strategy. To date, therapeutic cancer vaccines and immune checkpoint inhibitors are the two classes of immunotherapy that have demonstrated improvements in overall survival in patients with advanced tumors. The 2010 Food and Drug Administration approval of sipuleucel-T for asymptomatic or minimally symptomatic metastatic prostate cancer set the stage for ongoing phase III trials with the cancer vaccine PSA-TRICOM and the immune checkpoint inhibitor ipilimumab. A class effect of these approved immune-based therapies is a benefit in overall survival without short-term changes in disease progression, apparently due to modulation of tumor growth rate kinetics, in which the activated immune system exerts constant immunologic pressure that slows net tumor growth. A growing body of evidence suggests that the ideal population for clinical trials of cancer vaccines as monotherapy is patients with lower tumor volume and less aggressive disease. Combination strategies include immunotherapy with standard therapies or with other immunotherapies. Here we review emerging data on immunotherapy for patients with prostate cancer.

Tim-3: an emerging target in the cancer immunotherapy landscape.

The cancer immunotherapy field has grown exponentially in the past few years, largely driven by the success of immune checkpoint blockade. Therapies targeting the immune checkpoint molecules CTLA-4 and PD-1 have achieved objective responses in melanoma, renal cancer, and lung cancer; however, a large number of patients are still suffering with these cancers that are not benefiting from these therapies. Moreover, several cancers have proved to be largely refractory to therapies that target CTLA-4 and PD-1. This has catalyzed interest in targeting novel immune checkpoint receptors with the goal of realizing the full potential of checkpoint blockade for treating cancer. In this regard, the immune checkpoint receptor Tim-3 exhibits several unique features that make it an intriguing candidate for the next wave of therapies that target immune checkpoints in cancer.

From bench to bedside: immunotherapy for prostate cancer.

The mainstay therapeutic strategy for metastatic castrate-resistant prostate cancer (CRPC) continues to be androgen deprivation therapy usually in combination with chemotherapy or androgen receptor targeting therapy in either sequence, or recently approved novel agents such as Radium 223. However, immunotherapy has also emerged as an option for the treatment of this disease following the approval of sipuleucel-T by the FDA in 2010. Immunotherapy is a rational approach for prostate cancer based on a body of evidence suggesting these cancers are inherently immunogenic and, most importantly, that immunological interventions can induce protective antitumour responses. Various forms of immunotherapy are currently being explored clinically, with the most common being cancer vaccines (dendritic-cell, viral, and whole tumour cell-based) and immune checkpoint inhibition. This review will discuss recent clinical developments of immune-based therapies for prostate cancer that have reached the phase III clinical trial stage. A perspective of how immunotherapy could be best employed within current treatment regimes to achieve most clinical benefits is also provided.

Immunotherapy and therapeutic vaccines in prostate cancer: an update on current strategies and clinical implications

In recent years, immunotherapy has emerged as a viable and attractive strategy for the treatment of prostate cancer. While there are multiple ways to target the immune system, therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in late-stage clinical trials. The landmark Food and Drug Administration approval of sipuleucel-T for asymptomatic or minimally symptomatic metastatic prostate cancer set the stage for ongoing phase III trials with the cancer vaccine PSA-TRICOM and the immune checkpoint inhibitor ipilimumab. A common feature of these immune-based therapies is the appearance of improved overall survival without short-term changes in disease progression. This class effect appears to be due to modulation of tumor growth rate kinetics, in which the activated immune system exerts constant immunologic pressure that slows net tumor growth. Emerging data suggest that the ideal population for clinical trials of cancer vaccines is patients with lower tumor volume and less aggressive disease. Combination strategies that combine immunotherapy with standard therapies have been shown to augment both immune response and clinical benefit.

Evaluation of Ipilimumab in Combination With Allogeneic Pancreatic Tumor Cells Transfected With a GM-CSF Gene in Previously Treated Pancreatic Cancer

Preclinical reports support the concept of synergy between cancer vaccines and immune checkpoint blockade in nonimmunogenic tumors. In particular, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies have been successfully combined with GM-CSF cell-based vaccines (GVAX). Ipilimumab (anti-CTLA-4) has been tested as a single agent in patients with pancreatic ductal adenocarcinoma (PDA) resulting in a delayed response at a dose of 3 mg/kg. Our study evaluated ipilimumab 10 mg/kg (arm 1) and ipilimumab 10 mg/kg + GVAX (arm 2). A total of 30 patients with previously treated advanced PDA were randomized (1:1). Induction doses were administered every 3 weeks for a total of 4 doses followed by maintenance dosing every 12 weeks. Two patients in arm 1 showed evidence of stable disease (7 and 22 wk) but none demonstrated CA19-9 biochemical responses. In contrast, 3 patients in arm 2 had evidence of prolonged disease stabilization (31, 71, and 81 wk) and 7 patients experienced CA19-9 declines. In 2 of these patients, disease stabilization occurred after an initial period of progression. The median overall survival (OS) (3.6 vs. 5.7 mo, hazards ratio: 0.51, P = 0.072) and 1 year OS (7 vs. 27%) favored arm 2. Similar to prior ipilimumab studies, 20% of patients in each arm had grade 3/4 immune-related adverse events. Among patients with OS > 4.3 months, there was an increase in the peak mesothelin-specific T cells (P = 0.014) and enhancement of the T-cell repertoire (P = 0.031). In conclusion, checkpoint blockade in combination with GVAX has the potential for clinical benefit and should be evaluated in a larger study.