The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC’s Clinical/Translational Cancer Immunotherapy Section Co-Editor, James L. Gulley, MD, PhD, FACP.
“Engineering the TGFβ Receptor to Enhance the Therapeutic Potential of Natural Killer Cells as an Immunotherapy for Neuroblastoma,” by Rachel A. Burga et al. Translational Cancer Mechanisms and Therapy 2019 April 22
The inherently potent antitumor efficacy of natural killer (NK) cells is limited by immunosuppressive cytokines in the tumor microenvironment, such as TGFβ, which impair NK cell function and survival. Burga et al. hypothesized that by genetically modifying NK cells to express variant TGFβ receptors, immunosuppressive signaling would be diminished, allowing for therapeutic efficacy to be maintained even in the presence of such suppressive cytokines. This study presents data demonstrating the efficiency of using cord blood–derived NK cells modified to avoid the inhibitory effects of TGFβ as a way to harness innate immune cells for therapy. Such results provide evidence of enhanced antitumor activity in vitro and in vivo using allogeneic NK cells, suggesting the potential of a new treatment modality for patients with neuroblastoma which may impede TGFβ secretion as a potent immune evasion mechanism, leaving cancer cells vulnerable to NK-cell attack.
“Current Landscape of Immunotherapy in Breast Cancer,” by Sylvia Adams et al. JAMA Oncology 2019 April 11
With close to 300 clinical trials and the approval of atezolizumab (in combination with nab-paclitaxel) as the first FDA-approved immune checkpoint inhibitor (ICI) for the treatment of patients with metastatic triple-negative breast cancer (TNBC), there is a clear interest in developing immunotherapy-based treatment regimens for breast cancer. While tumors in the breast have previously been considered immunologically dormant compared with other tumor types, new findings highlight the opportunity to develop rational combinations of immune modulation with conventional or novel strategies for breast tumors that have minimal or no lymphocytic infiltrate. This review by Adams et al., found that immune checkpoint blockade is actually the most investigated form of immunotherapy in breast cancer and the use of ICI monotherapy has achieved objective, durable responses in breast cancer patients, with higher rates seen when administered in earlier lines of therapy. Results further suggest that optimization of immunotherapeutic agents in breast cancer will require not only a better understanding of inherent defects in the body’s immune response to breast tumors but also a more clear comprehension of corresponding clinical strategies to better induce an immune response, such as the effects of chemotherapy, targeted therapy, and radiation on immunologic aspects of the tumor microenvironment or the effect of vaccinating in the adjuvant setting or within a combination strategy.
“Estimation of the Percentage of US Patients With Cancer Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy Drugs,” by Alyson Haslam et al. JAMA Network Open 2019;2(5):e192535.
Between 2015 and 2017, the number of clinical trials using PD-1 and PD-L1 inhibitors has increased nearly 600%, from 215 trials to more than 1500, and the market is expected to grow from $1 billion dollars in 2013 to $7 billion dollars in 2020. Despite this growing interest in checkpoint inhibitors, empirical analyses have quantified the use of these drugs only in specific tumor types, with no known empirical analysis describing the potential use or benefit among all US patients with cancer. Haslam et al. sought to estimate what percentage of US patients with cancer are eligible to receive immune checkpoint inhibitor (ICI)-based therapy and what percentage of such patients might respond to ICI drugs. Results of this analysis demonstrate that if ICIs are universally available, approximately 44% of US patients with cancer could be eligible for such treatments, while at best, approximately 12.5% of patients with cancer in the United States are likely to respond to ICI treatment. These estimates, although modest, are actually better than estimates for oncology drugs in other classes, such as genome-targeted therapies, but should serve as motivation for researchers to further investigate biomarkers in order maximize the benefit of immunotherapy among patients receiving it.
“CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape,” by Mohamad Hamieh et al. Nature Letter 2019
Despite high complete response rates upon initial treatment, relapses occur in a large fraction of patients treated with chimeric antigen receptor (CAR) T cell therapy. Hamieh et al. used mouse models of leukemia to show that CARs provoke reversible antigen loss through trogocytosis, an active process in which the target antigen is transferred to T cells, thereby decreasing target density on tumor cells and abating T cell activity by promoting fratricide T cell killing and T cell exhaustion. This study demonstrated that tumor cells which are engaged but not killed by T cells are susceptible to trogocytic reduction of antigen density, with several possible consequences depending on different factors such as antigen density, the effector-to-target ratio and CAR design. Understanding these dynamic features provides a framework for rational CAR T cell dosing and combinatorial targeting strategies, including target-adapted CAR co-stimulatory functions.
“Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma,” by Noopur Raje et al. NEJM 2019 2 May; 380; 18
Even with advancements in therapies such as immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies, almost all patients with multiple myeloma eventually relapse. In previously reported pre-clinical studies, bb2121, a CAR T cell therapy that targets B-cell maturation antigen (BCMA), showed rapid, sustained elimination of tumors and 100% survival after single-dose administration in a mouse model of human multiple myeloma, suggesting potential long-term disease control in some incurable hematologic cancers. In the present study, Raje et al. presents initial results of a promising phase 1 clinical study of bb2121 anti-BCMA CAR T cells involving patients with heavily pretreated relapsed or refractory multiple myeloma. Reported objective response rate was 85%, including 45% with complete responses, and a median progression-free survival of 11.8 months. Furthermore, complete responses appeared to be associated with CAR T cell expansion, but independent of tumor BCMA expression, and were observed across all doses from 150x106 to 800x106 CAR T cells.
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