In situ vaccination by radiotherapy to improve responses to anti-CTLA-4 treatment

Abstract

Targeting immune checkpoint receptors has emerged as an effective strategy to induce immune-mediated cancer regression in the subset of patients who have significant pre-existing anti-tumor immunity. For the remainder, effective anti tumor responses may require vaccination. Radiotherapy, traditionally used to achieve local tumor control, has acquired a new role, that of a partner for immunotherapy. Ionizing radiation has pro-inflammatory effects that facilitate tumor rejection. Radiation alters the tumor to enhance the concentration of effector T cells via induction of chemokines, cytokines and adhesion molecules. In parallel, radiation can induce an immunogenic death of cancer cells, promoting cross-presentation of tumor-derived antigens by dendritic cells to T cells. Newly generated anti-tumor immune responses have been demonstrated post-radiation in both murine models and occasional patients, supporting the hypothesis that the irradiated tumor can become an in situ vaccine. It is in this role, that radiation can be applied to induce anti-tumor T cells in lymphocyte-poor tumors, and possibly benefit patients who would otherwise fail to respond to immune checkpoint inhibitors. This review summarizes preclinical and clinical data demonstrating that radiation acts in concert with antibodies targeting the immune checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4), to induce therapeutically effective anti-tumor T cell responses in tumors otherwise non responsive to anti-CTLA-4 therapy.

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.