Immunotherapy has revolutionized the systemic management of numerous malignancies. Nowhere has the proven benefit of these agents in clinical practice been more evident than in the management of advanced melanoma. Numerous preclinical studies have revealed the potential benefit of immune-priming radiotherapy in stimulating tumor-specific immune responses. This signal for immune activation may lead to clinically relevant synergy with immune checkpoint inhibitors against malignant cells. In this review, the authors summarize the current data outlining the role radiation therapy may play in the management of advanced melanoma alongside immune checkpoint inhibitors.
Key points
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Anti–cytotoxic T lymphocyte antigen 4 and anti–programmed cell death 1 agents are immune checkpoint inhibitors with a proven role in the management of advanced melanoma.
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Preclinical models have revealed radiation therapy to stimulate the immune system.
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Based on preclinical evidence, numerous prospective studies are currently underway to assess radiation therapy in the management of advanced melanoma alongside immune checkpoint inhibitors.
Introduction
Immunotherapy is shifting the oncologic landscape in the management of malignancies. The immune system plays a critical role in the body’s ability to clear neoplastic cells. Tumor evasion of the host immune system is crucial to its survival and proliferation. Through various mechanisms, tumors are able to evade the body’s innate and adaptive immune system. Immune checkpoint inhibitors (ICIs) are a new class of targeted agents, which directly target various machineries used by tumor cells to suppress the immune system. These drugs have displayed impressive results in both solid tumors and hematological malignancies. Nowhere have these impressive survival results been more detailed than in melanoma. Melanoma was the first tumor model to study the efficacy of ICIs. As a result, substantial survival benefits have been noted in the use of these agents over conventional chemotherapy.
The role of radiation therapy (RT) in advanced metastatic melanoma has traditionally been part of the larger effort to improve local tumor control either intracranially or extracranially. However, over the past decade studies have suggested the potential for RT to work synergistically with ICIs priming the immune system to enhance the efficacy of these systemic agents. Although the exact mechanism behind this synergistic effect is not known, several theories have been proposed. These theories include the use of RT microenvironment modification with cytokine and danger signal release resulting in immunogenic cell death. Multiple case reports have reported on the existence of such an effect whereby localized radiation alongside immunomodulating agents may have an effect in treating distant sites of disease. In addition, several case series detailing results both systemically and intracranially with combined modality management have been reported. The purpose of this review is to highlight the research, which has been conducted to date with ICIs alone and in combination with RT for the management of advanced melanoma.
Introduction
Immunotherapy is shifting the oncologic landscape in the management of malignancies. The immune system plays a critical role in the body’s ability to clear neoplastic cells. Tumor evasion of the host immune system is crucial to its survival and proliferation. Through various mechanisms, tumors are able to evade the body’s innate and adaptive immune system. Immune checkpoint inhibitors (ICIs) are a new class of targeted agents, which directly target various machineries used by tumor cells to suppress the immune system. These drugs have displayed impressive results in both solid tumors and hematological malignancies. Nowhere have these impressive survival results been more detailed than in melanoma. Melanoma was the first tumor model to study the efficacy of ICIs. As a result, substantial survival benefits have been noted in the use of these agents over conventional chemotherapy.
The role of radiation therapy (RT) in advanced metastatic melanoma has traditionally been part of the larger effort to improve local tumor control either intracranially or extracranially. However, over the past decade studies have suggested the potential for RT to work synergistically with ICIs priming the immune system to enhance the efficacy of these systemic agents. Although the exact mechanism behind this synergistic effect is not known, several theories have been proposed. These theories include the use of RT microenvironment modification with cytokine and danger signal release resulting in immunogenic cell death. Multiple case reports have reported on the existence of such an effect whereby localized radiation alongside immunomodulating agents may have an effect in treating distant sites of disease. In addition, several case series detailing results both systemically and intracranially with combined modality management have been reported. The purpose of this review is to highlight the research, which has been conducted to date with ICIs alone and in combination with RT for the management of advanced melanoma.
Anti–cytotoxic T lymphocyte antigen 4 therapy
Numerous receptors on the antigen-presenting cells and T cell are responsible for the immune response to tumor cells ( Fig. 1 ). Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a receptor expressed on the surface of T cells that interacts with CD80 and CD86 on antigen-presenting cells to downregulate the T-cell response on tumors. The anti–CTLA-4 monoclonal antibody, ipilimumab, inhibits the effect of the CTLA-4 receptor in inhibiting the immune response. The effect of CTLA-4 blockade is to allow CD28 (T cell) to bind to the B7-1 receptor (antigen-presenting cell), thus, allowing for immune stimulation and cytotoxic T-cell activation and proliferation. Following extensive preclinical and pilot studies, a phase II study was undertaken to assess the response to ipilimumab. A double-blind phase II study revealed a dose-dependent response with an overall response rate (ORR) of 11.0% for 10.0 mg/kg and 4.2% for 3.0 mg/kg but 0% for 0.3 mg/kg ( P = .0015). However, improved efficacy was also associated with increased adverse events. Phase III data have also revealed improved responses with ipilimumab. Ipilimumab ± glycoprotein100 peptide (gp100) vaccine was compared with gp100 vaccine monotherapy in patients with unresectable stage III or stage IV melanoma. Ipilimumab significantly improved overall survival (OS) compared with gp100 vaccine alone with a median OS of 10 months compared with 6.4 months in patients receiving the vaccine alone. Improved OS of approximately 2 months was also confirmed by a second randomized phase III trial assessing ipilimumab (10 mg/kg) and dacarbazine (850 mg/m 2 ) compared with dacarbazine (850 mg/m 2 ) plus placebo. A pooled analysis of data from 1861 patients enrolled in 10 prospective and 2 retrospective trials revealed that survival curves begin to plateau around 3 years after treatment. The rates of OS at 3 years were found to be 22%, 26%, and 20% for all, treatment-naive, and previously treated patients, respectively.
It should be noted that the response to ipilimumab can be preceded by an increase in diameter of tumor lesions owing to the distinct immune response patterns and T-cell recall at the tumor site. This unique response pattern makes clear the need for distinct evaluation criteria of treated lesions. In addition to response evaluation criteria in solid tumors (RECIST) criteria, the immune-related response criteria are often used to evaluate lesions treated with immunotherapy. Separate guidelines have been developed for the evaluation of cranial lesions treated with immunotherapy by the Response Assessment in Neuro-Oncology group.
Anti–programmed cell death 1 therapy
Following chronic T-cell activation, the inhibitory receptor programmed cell death 1 (PD-1) is induced on T cells, which engages with one of its ligands, programmed death-ligand 1 (PD-L1), found on tissue-based macrophages, antigen-presenting cells, and tumor cells. This interaction along the PD-1/PD-L1 axis mediates the immune escape of tumor cells by promoting T-cell exhaustion. PD-L1 is expressed in various tumors, is thought to be one of the main mechanisms of immune escape, and is associated with worse prognosis. The discovery of the PD-1/PD-L1 axis led to the development of specific anti–PD-1 inhibitors. Two anti–PD-1 inhibitors, the monoclonal antibodies nivolumab (a fully human anti–PD-1 immunoglobulin G4 [IgG4]) and pembrolizumab (a humanized anti–PD-1 IgG4) have both gained widespread use in the management of advanced melanoma. Several phase III studies have confirmed improved response rates with anti–PD-1 therapy. A randomized study of nivolumab versus dacarbazine in BRAF wild-type untreated melanoma revealed a superior ORR of 40% versus 14% with an improved OS rate of 73% versus 42%. Improved toxicity profiles were also noted with anti–PD-1 therapy with a 12% treatment-related adverse effect rate versus 18% with dacarbazine. In the CheckMate 037 phase III trial, patients were randomly assigned 1:2 to either the investigator’s choice of chemotherapy or to nivolumab 3 mg/kg every 2 weeks. In the first reported interim analysis, objective responses were reported in 32% of the first 120 patients in the nivolumab group and 11% of the 47 patients in the investigator’s choice group. The rate of grade 3 to 4 drug-related adverse events was fairly similar between the two groups: 5% and 9% in nivolumab and chemotherapy groups, respectively.
The efficacy of pembrolizumab has also been well studied in the management of advanced-stage melanoma. KEYNOTE-002 was a phase II study assessing 2 different doses of pembrolizumab, including 2 mg/kg and 10 mg/kg, compared with investigator’s choice chemotherapy. Results revealed an improvement in progression-free survival (PFS) at 6 months as assessed by independent central review. Grade 3 to 4 treatment-related adverse events were more common in patients receiving chemotherapy than pembrolizumab. Improved rates of PFS were noted with pembrolizumab compared with ipilimumab in a large phase III randomized study of 834 patients. Patients were randomized to 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or to 4 doses of ipilimumab 3 mg/kg every 3 weeks. The 6-month PFS rates were 47%, 46%, and 27%, respectively, with 1-year OS rates of 74%, 68%, and 58%, respectively. Treatment-related adverse events (grades 3–5) were slightly lower in the pembrolizumab groups: 13% and 10% versus 20% with ipilimumab.
Combination therapy with anti–programmed cell death 1 and anti–cytotoxic T lymphocyte antigen 4 agents
Combining ICIs in various sequences offers a new treatment option in the management of advanced melanoma. Data have revealed that combined therapy may offer improved results over single-agent therapy alone. In a double blind study of 142 patients who were previously untreated, patients were randomly assigned 2:1 to receive ipilimumab (3 mg/kg) combined with nivolumab (1 mg/kg) or placebo once every 3 weeks for 4 doses followed by nivolumab 3 mg/kg or placebo every 2 weeks until disease progression or severe toxicity. In patients with BRAF wild-type tumors, ORR was 61% in the group that received both ipilimumab and nivolumab versus 11% in the group that received ipilimumab and placebo. Median PFS was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy groups. These results were similar to those obtained in 3 patients with BRAF mutated tumors. These results are similar to another phase III study involving 945 patients who were randomized 1:1:1 to either ipilimumab or nivolumab alone or to combination therapy in stage III or IV melanoma. Patients treated with the combination therapy had a PFS of 11.5 months, compared with 2.9 months for those treated with ipilimumab alone and 6 months for those treated with nivolumab alone. However, combination therapy was associated with a higher incidence of grade 3 to 4 immune-related adverse events commonly involving more than one organ. Combination therapy was also compared with ipilimumab alone in treatment-naive patients in the phase II CheckMate 064 study. In this trial, 2 sequences of combination therapy were tested. These regimens included ipilimumab followed by nivolumab versus nivolumab followed by ipilimumab. The response rate was higher for the latter sequence: 41% versus 20% with a higher 12-month OS rate of 76% versus 54%. This study suggests that the sequence of treatment with combined immune checkpoint inhibition effects outcomes with improved response and survival noted with nivolumab followed by ipilimumab.
Radiation therapy and immune checkpoint inhibitors: preclinical data
RT has long been a standard component of the treatment paradigm for many solid malignancies with curative or palliative intent, including melanoma. The effect of radiation on DNA damage has been thought to be from the generation of double-strand breaks leading to mitotic and apoptotic cell death. However, evidence also suggests the immune system plays a larger influence on the response of malignant cells to radiation. A robust immune system has been shown to play an important role in RT’s effect, with studies revealing that in T-cell–deficient mice, tumor control by RT is reduced compared with those mice that are immunocompetent. The study by Lugade and colleagues revealed immune responses in mice after treatment of B16 melanoma with single 15-Gy or fractionated 5 × 3-Gy doses of RT ( Table 1 ). Irradiated mice were more capable of presenting tumor antigens and specific T cells secreting interferon (IFN)-C on peptide stimulation within tumor draining lymph nodes than nonirradiated mice. Activation of the immune system in lymph nodes correlated with an increase in the CD45+ cells infiltrating single dose irradiated tumors compared with nonirradiated mice. Other studies have also revealed the influence of RT enhancing major histocompatibility complex class I (MHC-I) expression and inducing antitumor immunity and the radiation-induced IFN-gamma production within the microenvironment of the tumor. In addition, the absence of toll-like receptor signaling has been shown to impair the effect of RT-mediated tumor control. RT has been shown to prime the immune system augmenting T-cell activation.
| Author, Year of Publication | Key Points |
| Lugade et al, 2005 | Irradiated mice are more capable of presenting tumor antigens and T cells secreting IFN-C on peptide stimulation within tumor draining lymph nodes than nonirradiated mice. |
| Reits et al, 2006 | Cell surface expression of MHC class I molecules was increased for many days in a radiation dose-dependent manner. Immunotherapy was successful in eradicating a murine colon adenocarcinoma only when preceded by radiotherapy of tumor tissue. |
| Dewan et al, 2009 | Fractionated rather than single-dose radiation found to produce immune mediated abscopal effect alongside anti–CTLA-4 therapy with the same effect locally. |
| Apetoh et al, 2008 | Patients with breast cancer who carry a toll-like receptor 4 (TLR4) loss-of-function allele relapse quicker after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. |
| Matsumura et al, 2008 | Radiation enhances recruitment of CD8 T cells in mouse and human breast cancer cell lines through the chemokine CXCL16. |
| Deng et al, 2014 | PD-L1 is upregulated in the tumor microenvironment following RT with a reduction in the local accumulation of tumor-infiltration myeloid-derived suppressor cells. |
| Twyman-Saint Victor et al, 2015 | Differing roles of RT and ICIs were noted with anti–CTLA-4 inhibiting Treg cells, RT enhanced diversity of T-cell repertoire of intratumoral T cells, and PD-L1 blockade reversed T-cell exhaustion. |
The immunomodulatory effects of RT have also been associated with cross presentation of tumor-derived antigens by dendritic cells. The activation of T-cell response requires the cross presentation of these antigens with type I IFN. Through upregulation of the MHC-I, adhesion molecules, death receptors, and NKG2D ligands, which enable identification and elimination of damaged cancer cells, RT is also able to initiate the effector phase by recruiting effector T cells at the tumor site. However, radiation may also have immunosuppressive effects. It has been noted that regulatory T cells (Tregs) are more radioresistant than conventional T-cells and are upregulated following RT. Tregs play an important immunosuppressive role in antitumor immunity. In addition, RT can enhance tumor infiltration by myeloid-derived suppressor cells, which are responsible for sustaining chronic immunosuppression. It has also been shown that RT can induce Langerhans cells to migrate to the lymph nodes from the skin where they upregulate Tregs. Given both these immunosuppressive and immunostimulatory effects, it is no surprise that the use of RT is a unique interplay between both the upregulation and downregulation of effects on the immune system and their effects on ICIs. The balance between these signals determines the direct effect RT will have alongside ICIs in tumor management. Therefore, understanding how RT can be optimized in terms of total dose, fractions, and timing to enhance the immunogenicity of ICIs is key.
Preclinical models have revealed the potential of RT to enhance the efficacy of anti–PD-1 therapy. Deng and colleagues demonstrated PD-L1 to be upregulated in the tumor microenvironment following RT. Concomitant with RT-mediated tumor regression, combined therapy reduced the local accumulation of tumor-infiltrating myeloid-derived suppressor cells, which suppress T-cell action against tumors. Twyman-Saint Victor and colleagues have suggested further preclinical support for combined modality management and ICIs. The group reported optimal response to management with combined therapy with ICIs and RT, noting anti–CTLA-4 predominantly inhibits Treg cells and RT enhances the diversity of the T-cell receptor repertoire of intratumoral T cells. Together, anti–CTLA-4 promotes expansion of T cells, whereas radiation shapes the T-cell receptor repertoire of the expanded peripheral clones. The addition of PD-L1 blockade reverses T-cell exhaustion. These results paralleled findings in patients on a melanoma clinical trial at the institution. These findings support the distinct but complementary roles ICIs and RT have in tumor regression.
The optimal radiation dose to enhance immunogenicity remains an open question. The use of fractionated radiation has been shown to be more immunogenic than single-dose radiation with a dose of 24 Gy in 3 fractions or 30 Gy in 5 fractions inducing an immune-mediated abscopal effect alongside anti–CTLA-4 therapy with the same effect locally. However, the benefits of fractionated radiation were not observed in another study by Lugade and colleagues, which revealed 15 Gy in 5 fractions to be inferior to 15 Gy in 1 fraction in primary tumor control with equivocal T-cell activation. Moving forward, it will be important for us to better understand the underlying relationship of radiation fractionation and immunogenicity in order to take advantage of the priming effect of radiation to induce the greatest immunogenicity from ICIs.
Radiation therapy and immune checkpoint inhibitors: systemic clinical data
Case Reports
One of the prime areas in which involvement of the immune system with RT has been observed is the bystander effect or the abscopal effect whereby local radiation can prompt a response in tumor cells outside the radiation field. Several cases have been reported since that time on complete responses to disease outside the irradiated field using combined modality treatment and are summarized in Table 2 . The abscopal effect was first reported by Mole in 1953 and has subsequently been reported in numerous tumor types. Although the exact mechanism by which the abscopal effect takes place remains to be elucidated, there is a suggestion that the immune system plays a critical role. Local radiation elicits a large, immune-mediated systemic response implicated by local inflammatory reactions that can unmask tumor antigens. A sudden reappearance of these antigens by tumor can stimulate the immune system to identify previously unrecognized tumor antigens. Studies have now revealed that in addition to the classic radiation-mediated generation of free radicals leading to DNA double-strand breaks, in vivo radiation may also induce immunologic cell death. Radiation damage may lead to an increased release of damage-associated molecular patterns, which, when engulfed by antigen-presenting cells, present these to T cells, thereby initiating an immune response.
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