Current Clinical Trials Testing Combinations of Immunotherapy and Radiation

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Preclinical evidence of successful combinations of ionizing radiation with immunotherapy has inspired testing the translation of these results to the clinic. Interestingly, the preclinical work has consistently predicted the responses encountered in clinical trials. The first example came from a proof-of-principle trial started in 2001 that tested the concept that growth factors acting on antigen-presenting cells improve presentation of tumor antigens released by radiation and induce an abscopal effect. Granulocyte-macrophage colony-stimulating factor was administered during radiotherapy to a metastatic site in patients with metastatic solid tumors to translate evidence obtained in a murine model of syngeneic mammary carcinoma treated with cytokine FLT-3L and radiation. Subsequent clinical availability of vaccines and immune checkpoint inhibitors has triggered a wave of enthusiasm for testing them in combination with radiotherapy. Examples of ongoing clinical trials are described in this report. Importantly, most of these trials include careful immune monitoring of the patients enrolled and will generate important data about the proimmunogenic effects of radiation in combination with a variety of immune modulators, in different disease settings. Results of these studies are building a platform of evidence for radiotherapy as an adjuvant to immunotherapy and encourage the growth of this novel field of radiation oncology.

Introduction

Although evidence for contribution of the immune system to the clinical response of radiotherapy dates as far back as the mid-1970s,1 it is only in the past 10 years that trials have started exploring this novel approach in the clinic. For instance, there is now some evidence of tumor-specific immunity in patients following radiation. In one study, it was demonstrated that radiotherapy and antiandrogen hormone therapy induced autoantibody responses to a variety of tumor-associated antigens (Ags) in 25%-30% of patients with prostate cancer.2 In another study, after radiation some patients with colorectal cancer or prostate cancer had T cells specific for an Ag that is overexpressed by tumors detectable by tetramer analysis.3 The host’s recruited immune response against the irradiated tumor has the potential to actively contribute to the success of the course of radiotherapy.

Moreover, if sufficiently robust, this newly acquired immune response could achieve systemic antitumor effects. In this scenario, tumor-specific effector T cells can target cancer cells at metastatic sites, achieving an abscopal effect of radiotherapy (ab scopus = away from the target).4, 5 Clinical abscopal effects of radiotherapy have been described, although very uncommon.4 Their rare occurrence reflects the fact that by itself, standard radiotherapy is inadequate at subverting the existing immunosuppression or tolerance characteristic of the microenvironment of an established tumor. However, the ability of radiation to prime antitumor responses is likely to be key in obtaining a therapeutic synergy with immunotherapies that can unleash these immune responses.

The first trial testing the ability of a combination of radiation and immunotherapy to induce abscopal responses, a proof-of-principle trial that has opened this field, is described in the following sections.6 A brief summary of the ongoing trials of immunotherapy and radiation that are currently open for patient enrollment is given. Without the ambition of representing all the ongoing research on the subject, this report is meant to offer some examples of current investigations in this field and introduce the reader to some of the challenges intrinsic to the combination of the 2 modalities.

Section snippets

Initial Trials of Radiotherapy and Immunotherapy

Investigators at New York University (NYU) originally hypothesized that ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated, reporting out of the field responses in a murine model of syngeneic mammary carcinoma treated with FLT-3L and radiation.5

The same group conducted the first “proof-of-principle” trial, exploring the combination of subcutaneous (s.c.) administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) with chemoradiotherapy

NYU Trials of Immunotherapy and Radiation

Currently, 4 institutional review board (IRB)–approved, investigator-initiated trials combining radiotherapy and immunotherapy are ongoing at NYU (Table 1).

Earle A. Chiles Research Institute, Providence Cancer Center (Providence Portland Medical Center, Oregon), Trials of Immunotherapy and Radiation

Currently, 5 IRB-approved, investigator-initiated trials combining radiotherapy and immunotherapy are ongoing at Chiles Research Institute (Table 2).

Stanford Trials of Immunotherapy and Radiation

In 2007, Stanford reported that in a murine model of a widely metastatic B-cell lymphoma, the combination of chemotherapy plus intratumoral injection of oligodeoxynucleotides containing unmethylated C-G motifs (CpG), a TLR9 agonist, could completely eradicate the inoculated tumor. This therapeutic effect required that the CpG be injected directly into the tumor and was dependent on CD8 T cells. Although the efficacy of CpG oligodeoxynucleotides has been thought to depend on the expression of

NCT01496131/NIH 11-C-0247 “Deprivation Therapy and Radiation Therapy for Untreated, Intermediate and High-risk Prostate Cancer Patients”

NCT01496131 is a phase II trial designed to determine the effect of L-BLP25/tecemotide, a vaccine that is designed to elicit immune responses to MUC-1 on tumor cells, in addition to standard treatment on the MUC1-specific systemic immune response in patients with newly diagnosed high- or intermediate-risk prostate cancer L-BLP25 vaccine in combination with androgen-deprivation therapy and XRT. Prior studies with this immunotherapy for stage III NSCLC29 showed an apparent improvement in efficacy

Thomas Jefferson University Radiation and Immunotherapy Trials

Investigators at Thomas Jefferson University (TJU) are currently testing the combination of ipilimumab (anti–CTLA-4) with radiation in brain metastases from melanoma.

Based on the hypothesis that treatment with high doses of XRT would result in tumor cell death, releasing tumor debris and liberating potential tumor Ags, investigators at TJU designed a trial that combines XRT with ipilimumab. The idea is that ipilimumab will facilitate immune recognition of these novel tumor-specific Ags,

Conclusions

The listed ongoing trials in 7 distinct tumor sites, at different stages of disease, represent a snapshot of some of the ongoing research testing in patients with cancer the feasibility and efficacy of combining radiotherapy and immunotherapy. These trials are initial explorations and represent the beginning of a new era of research. Importantly, they often test the combination in a metastatic setting, a stage where radiotherapy is traditionally reserved for palliation of symptoms. If these

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    Conflicts of interest: Prometheus Pharmaceuticals has given financial support for the Phase II IL-2 study with radiation from EACRI (M.C.).

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