Current Clinical Trials Testing Combinations of Immunotherapy and Radiation
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
References (29)
- et al.
Systemic effects of local radiotherapy
Lancet Oncol
(2009) - et al.
Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated
Int J Radiat Oncol Biol Phys
(2004) - et al.
In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation; a phase 1/2 study
Blood
(2012) - et al.
Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial
Lancet Oncol
(2014) - et al.
Combination of local irradiation with systemic application of anaerobic corynebacteria in therapy of a murinefibrosarcoma
Cancer Res
(1975) - et al.
Standard treatments induce antigen-specific immune responses in prostate cancer
Clin Cancer Res
(2007) - et al.
Phase I study of a vaccine using recombinant vaccinia virus expressing PSA (rV-PSA) in patients with metastatic androgen-independent prostate cancer
Prostate
(2002) - et al.
T-cell responses to survivin in cancer patients undergoing radiation therapy
Clin Cancer Res
(2008) - et al.
Topical TLR7 agonist imiquimod can induce immune-mediated rejection of skin metastases in patients with breast cancer
Clin Cancer Res
(2012) - et al.
Synergy of topical toll-like receptor 7 agonist with radiation and low-dose cyclophosphamide in a mouse model of cutaneous breast cancer
Clin Cancer Res
(2012)
Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer
Clin Cancer Res
Fractionated but not single dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody
Clin Cancer Res
Suppressing T cell motility induced by anti-CTLA-4 monotherapy improves antitumor effects
J Clin Invest
Immunologic correlates of the abscopal effect in a patient with melanoma
N Engl J Med
Cited by (119)
Relationship between the tumor microenvironment and the efficacy of the combination of radiotherapy and immunotherapy
2023, International Review of Cell and Molecular BiologyEuropean consensus-based interdisciplinary guideline for melanoma. Part 2: Treatment - Update 2022
2022, European Journal of CancerMathematical modeling of radiotherapy and its impact on tumor interactions with the immune system
2022, Neoplasia (United States)Citation Excerpt :A similar trial, NCT03223155, is focused on the sequencing of ipilimumab, nivolumab and SBRT for NSCLC with estimated completion in December 2022. More in-depth discussions of clinical trials investigating the combination of radiotherapy and immunotherapies can be found elsewhere [8–10]. While these clinical studies provide invaluable insights into selected protocols, to exhaustively evaluate every possible radiation dose and dose fractionation with different sequencing and timing of the various immuno-therapeutics remains infeasible [61].
Radiation and Modulation of the Tumor Immune Microenvironment in Non–Small Cell Lung Cancer
2021, Seminars in Radiation Oncology
Conflicts of interest: Prometheus Pharmaceuticals has given financial support for the Phase II IL-2 study with radiation from EACRI (M.C.).