In situ vaccination by radiotherapy to improve responses to anti-CTLA-4 treatment
Introduction
From the inception of carcinogenesis, the immune system detects and eliminates nascent tumors in a process described as cancer immunosurveillance. Stress-induced ligands and altered antigenicity render transformed cells susceptible to natural killers (NK) cells, γδ and conventional α/β T cells. Tissue disruption and unscheduled cell death that occur during tumor progression to invasion generate dangers signals in the form of damage-associated molecular pattern (DAMP) molecules that alert the immune system of a potential threat, activating both innate and adaptive immunity [1]. However, occasionally elimination of cancer cells is incomplete and cancer cells that have acquired the ability to evade immune control emerge, as a result of the selective pressure of the immune system. Thus, cancers rise to clinical detection after a long and complex crosstalk with the immune system, while a dominant immune suppressive tumor micro-environment has also emerged. The latter is enriched in cells with regulatory and immunosuppressive function that secrete cytokines such as transforming growth factor-β (TGFβ) and IL-10, which counteract immune-mediated rejection [2]. Noticeably, in some patients robust anti-tumor T cell responses are detectable at clinical diagnosis and their presence in the tumor specimen has been associated with a better prognosis [3], [4]. Patients who retain such anti-tumor immunity appear to benefit the most from immunotherapy, even at advanced stages of the disease [5]. For example, responses to immune checkpoint inhibitors rely on the patient's pre-existing anti-tumor T cells [6], [7]. Unfortunately, only a small fraction of cancer patients retains sufficient anti-tumor immune responses. Among solid tumors patients, melanoma carriers are most likely to respond to immune checkpoint inhibitors targeting CTLA-4 or programmed cell death-1 (PD-1) [8], [9], possibly because of their high mutational load [10].
Because responses to anti-CTLA-4 often are durable [11], [12], identifying combination treatments that can convert patients unresponsive to CTLA-4 inhibition into responders is an active area of investigation. Potential candidates include other immunotherapies, standard chemotherapy, targeted agents [13], [14], [15], and radiotherapy has earned a prominent place, due to substantial pre-clinical data [16], [17], [18], [19], [20] and rapidly accumulating clinical observations [21], [22], [23] that it can induce therapeutically effective anti-tumor immunity when combined with CTLA-4 blockade. Several clinical trials are currently ongoing to test radiotherapy in combination with the FDA-approved anti-CTLA-4 antibody ipilimumab (Yervoy®, Bristol Meyers-Squibb, New York, New York) (Table 1).
Here we review the available data that has informed the rationale for exploiting the synergy of radiation and CTLA-4 blockade.
Section snippets
Radiation-induced in situ tumor vaccination
Over the past decade, an improved understanding of the effects of local radiation on tumor-host interactions has led to the recognition that radiotherapy may have a novel role as an inducer of acute inflammation and immunogenic cell death, capable to convert a tumor into an in situ vaccine [24], [25], [26]. Pioneering work implicating T cells in determining the response to radiation was published several decades ago [27]. More recently, the demonstration that T cells mediate the abscopal effect
Cytotoxic T lymphocyte antigen-4, a negative regulator of T-cell activation
An array of co-stimulatory and co-inhibitory molecules regulates T cells activation, balancing the need to eliminate pathogens with the prevention of autoimmunity [71]. T cell activation requires two signals, the first is delivered by TCR binding to MHC-I/antigen. The second is delivered by CD28 costimulatory receptor that binds to CD80 (B7–1) and CD86 (B7–2) on the surface of antigen presenting cells (APC), resulting in abundant secretion of IL-2 and T-cell proliferation [72].
After TCR
Synergy of radiotherapy with anti-CTLA-4 antibody
Previous work in pre-clinical models of melanoma and breast cancer showed that tumors insensitive to anti-CTLA-4 treatment as monotherapy became responsive upon vaccination with modified autologous tumor cells [89], [90]. We hypothesized that in situ vaccination by radiation could also convert a poorly immunogenic tumor, unresponsive to anti-CTLA-4 into a responder. This hypothesis was confirmed in three different murine tumor models, 4T1 and TSA mammary carcinomas syngeneic to BALB/c mice and
Clinical translation
Since 2011, after the approval of ipilimumab for patients with metastatic or unresectable melanoma, a few dramatic abscopal responses have been reported after radiation of one metastasis in patients who were unresponsive or had ceased to respond to ipilimumab [21], [22], [93]. These reports have sparked several retrospective analyses of outcome in melanoma patients receiving radiation while treated with ipilimumab, with an excellent review of these studies recently published by Barker and
Conclusions
The ability of radiation to elicit anti-tumor immune responses has been unequivocally demonstrated in experimental models, and many of the mechanisms involved have been identified. However, more work is required to define the dose(s) and fractionation that optimally induce anti-tumor T cells, and identify the tumor characteristics that predict which tumors will respond to a given combination of radiation and immune checkpoint blockade. While the growing number of reports of occasional abscopal
Conflict of interest statement
The authors declare that no conflict of interest exists.
Acknowledgements
The authors are grateful to Sophia Ceder (www.ceder.graphics) for illustrating Fig. 1. SD 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. CV-B is supported by a Post-doctoral fellowship from the Department of Defense Breast Cancer Research Program (W81XWH-13-1-0012). SCF is supported by grants from USA Department of Defense Breast Cancer
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