Combination of Radiotherapy and Immune Checkpoint Inhibitors☆,☆☆
Introduction
Antigens recognized by T cells in tumors include differentiation antigens, overexpressed antigens, cancer-testis, and mutated tumor neoantigens.1 Only antigens in the last category are truly tumor specific, whereas the other antigens are expressed at low levels or in a restricted fashion in normal adult tissues or during development and are often referred to as “tumor-associated” antigens. Because tumor-associated antigens are shared between multiple tumors and patients, they have been the focus of most vaccination strategies. However, clinical responses have been limited even when antigen-reactive T cells were successfully induced by the vaccine.2 In part, this may be because such self-antigens can only elicit weak responses as strongly reactive T cells are usually deleted during ontogeny. In addition, because of their intrinsic genomic instability, cancer cells can escape cytotoxic T lymphocyte (CTL) recognition by mutation or downregulation of the antigens, just as they almost inevitably develop resistance to targeted therapeutics. In fact, the process of immunoediting of antigens expressed by tumors occurs spontaneously during cancer development.3 Tumors arising in immunocompetent hosts lose the most immunogenic antigens under the pressure of the immune system to escape immune control.4
Importantly, the same process that allows immune escape also generates a plethora of mutated neoantigens that are more immunogenic than differentiation or overexpressed antigens.5, 6 Tumors with the highest degree of genomic instability often also have a more prominent lymphocytic infiltrate.7, 8 They escape immune control by recruiting immunosuppressive and regulatory host cells, producing immunosuppressive cytokines and other mediators, and by expressing surface ligands that inhibit CTL action.9 Perhaps not surprisingly, tumors with an immune-active microenvironment are more likely to respond to immunotherapy agents that target key immunosuppressive pathways.10 The remarkable clinical responses to treatment with anti–CTL antigen-4 (CTLA-4) or anti–programmed death (PD)-1 antibodies or both observed in metastatic melanoma, a tumor with a high mutational burden, illustrates this concept.11, 12, 13
However, responses to immune checkpoint inhibitors are seen only in a fraction of patients with melanoma and other cancers. Efforts to identify combination treatment that can convert nonresponders into responders who could enjoy the long-term benefits of immunotherapy are ongoing.14 As part of this effort, radiotherapy is being tested in combination with the Food and Drug Administration–approved anti–CTLA-4 antibody ipilimumab (Yervoy, Bristol Meyers-Squibb, New York, NY) in at least a dozen trials (www.clinicaltrials.gov). Herein, we review the preclinical data that provide a rationale for testing radiotherapy as potentially an ideal partner for immune checkpoint inhibitors and discuss the initial clinical observations that support a synergy between radiation and anti–CTLA-4 therapy.
Section snippets
Evidence That Local Radiotherapy Can Generate an In Situ Tumor Vaccine
Ionizing radiation causes damage to multiple biomolecules by direct energy deposition or by generation of free radicals, leading to cell death when the damage cannot be repaired.15 Tumor cell death induced by radiation is usually preceded by cell stress and, depending on the degree of alteration of survival and apoptosis pathways and of cell cycle regulatory mechanisms, can occur via different pathways.16 However, it is likely that at least a portion of the cancer cells within a tumor will die
Cytotoxic T Lymphocyte Antigen-4
CTLA-4 (CD152) is a master regulator of T-cell activation that plays a key role in maintaining tolerance to self-antigens, as demonstrated by the development of lymphoproliferative disease with massive T-cell infiltration of multiple organs in CTLA-4 knockout mice.37, 38 However, in the immunosuppressive microenvironment of cancer, CTLA-4 becomes an obstacle to the activation and function of antitumor T cells. T-cell activation is initiated when T-cell receptors (TCR) bind to antigenic peptide
CTLA-4 blockade
In a seminal study, antibody-mediated blockade of CTLA-4 was shown to induce effective antitumor immunity in mice.62 The therapeutic effect, however, was limited to relatively immunogenic tumors. Less immunogenic tumors, including the B16 mouse melanoma model, required the addition of a vaccine to anti–CTLA-4 antibody to achieve tumor rejection63. For patients with metastatic melanoma, anti–CTLA-4 mAbs have shown clinical benefits as single agents.11 Although the percentage of patients
Conclusions
The well-orchestrated expression of negative regulatory molecules in immune cells prevents unrestricted T-cell activation that can potentially lead to immunopathology. In cancer, these immune checkpoint pathways are disregulated and tend to be overexpressed, preventing tumor rejection. Preclinical and clinical data have demonstrated that even in advanced cancer resistant to other treatment, these inhibitory receptors can be successfully targeted therapeutically. Importantly, radiotherapy is
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S.D. is supported by Grants from the USA Department of Defense Breast Cancer Research Program (W81XWH-11-1-0532), The Chemotherapy Foundation, Breast Cancer Alliance, and Breast Cancer Research Foundation. C.V.-B is supported by a Postdoctoral fellowship from the Department of Defense Breast Cancer Research Program (W81XWH-13-1-0012).
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The authors declare no conflict of interest.