Trial Watch: Immunotherapy plus radiation therapy for oncological indications

Abstract

Malignant cells succumbing to some forms of radiation therapy are particularly immunogenic and hence can initiate a therapeutically relevant adaptive immune response. This reflects the intrinsic antigenicity of malignant cells (which often synthesize a high number of potentially reactive neo-antigens) coupled with the ability of radiation therapy to boost the adjuvanticity of cell death as it stimulates the release of endogenous adjuvants from dying cells. Thus, radiation therapy has been intensively investigated for its capacity to improve the therapeutic profile of several anticancer immunotherapies, including (but not limited to) checkpoint blockers, anticancer vaccines, oncolytic viruses, Toll-like receptor (TLR) agonists, cytokines, and several small molecules with immunostimulatory effects. Here, we summarize recent preclinical and clinical advances in this field of investigation.

Role of the immunosuppressive microenvironment in immunotherapy

“…Hundreds of active phase 2 and 3 clinical trials are evaluating novel immune therapies and concurrent immune therapy combinations targeting the immunosuppressive TME. A comprehensive listing of active trials is beyond the scope of this review, and readers are directed to serial publications aimed at reviewing such trials for further edification 72, 73. The results from these trials will guide future studies of novel targeted immune therapies and immune therapy combinations.…”

Immune recognition of irradiated cancer cells

“…Multiple clinical trials are currently testing the combination of RT with FDA‐approved checkpoint blockers, including ipilimumab, nivolumab, pembrolizumab, and atezolizumab, and robust responses have been reported in this setting . Although the main rationale of this strategy is to improve the response rate of patients treated with checkpoint blockers (which is generally low), potential synergistic effects may also relate to the offset of RT‐induced PD‐L1 or CD80 upregulation .…”

Trial Watch: Immunostimulatory monoclonal antibodies for oncological indications

“…6,[41][42][43][44][45][46][47] Accordingly, no less than 6 of these agents are currently approved by the US Food and Drug Administration (FDA) or equivalent regulatory agencies worldwide for use in one or multiple oncological indications. [48][49][50] At least in part, the unprecedented clinical success of ICBs reflects the high expression of co-inhibitory receptors such as cytotoxic lymphocyte-associated protein 4 (CTLA4) and programmed cell death 1 (PDCD1; best known as PD-1) by tumor-infiltrating lymphocytes, combined with a relative abundance of their cognate ligands -i.e., CD80, CD86 and CD274 (best known as PD-L1)in the tumor microenvironment. 42,51,52 However, a considerable fraction of cancer patients displays innate or acquired resistance to ICB-based immunotherapy (owing to a variety of mechanisms), [53][54][55][56][57][58][59][60] calling for the development of alternative strategies to reverse immunosuppression and (re) enable tumor-targeting immune responses.…”

“…42,51,52 However, a considerable fraction of cancer patients displays innate or acquired resistance to ICB-based immunotherapy (owing to a variety of mechanisms), [53][54][55][56][57][58][59][60] calling for the development of alternative strategies to reverse immunosuppression and (re) enable tumor-targeting immune responses. 42,49,[61][62][63][64][65][66] One of these approaches is based on mAbs or fusion proteins that operate as agonists for co-stimulatory receptors expressed by CTLs, NK cells, CD4 C helper T cells, or APCs (Table 1). [67][68][69][70][71] The most relevant receptors in this setting are CD27, [72][73][74] CD28, [75][76][77] CD40, [78][79][80][81][82] TNF receptor superfamily, member 4 (TNFRSF4; best known as OX40), [83][84][85] TNF receptor superfamily member 9 (TNFRSF9; best known as CD137 or 4-1BB), [86][87][88][89] TNF receptor superfamily member 18 (TNFRSF18; best known as GITR), [90]…”