Studies have shown RT efficacy in the treatment of melanoma dating back to the 1970s.1,2 Typically, it is used in the context of adjuvant therapy following resection in early stage disease or as palliation in late stage i.e., spinal cord compression, brain metastasis, or metastasis causing pain, bleeding, or obstruction. RT local clinical benefit relies on induced DNA damage causing apoptosis.3 Abscopal effect refers to a rare phenomenon of tumor regression at a site distant from the primary site of RT and has been shown in multiple cancers including melanoma.4–7 There is renewed interest in the immunomodulatory effects of RT in the era of immunotherapy because pre-clinical models suggest that RT can improve efficacy of immune checkpoint blockade and conversely ICI can increase the efficacy of RT not only locally but systemically.8–10 Research shows that triple therapy (RT + anti-CTLA-4 + anti-PD-1/PD-L1) such as what was used in our patients is not redundant and is instead complimentary. Clinical models suggest that RT increases diverse T cell activation through increased local expression of MHC class 1 molecules which improves the antigen presenting ability of APCs.11–13 Then CTLA-4 blockade initiates the suppression of Treg cells, thus increasing the ratio of CD8/ Treg and the addition of PD-1/PD- L1 inhibition increases the proportion of overall CD8 + T cells.14 These activated CD8 + T cells can migrate through the body and infiltrate the metastases outside of the irradiated field when a certain threshold amount is reached causing systemic anti-tumor benefit.14
Still, very little is understood clinically about combination RT + anti-CTLA-4 + anti-PD-1/PD-L1. A 24 patient pilot study of RT in combination with NIVO/IPI in locally advanced head and neck squamous cell carcinoma showed feasibility of RT with ICI and resulted in no loco-regional relapses in 20 high-risk patients. No patients in the study developed grade 4/5 adverse events during combination therapy.15 Similarly, a prospective study of Durvalumab (anti-PD-L1) and Tremelimumab (Anti-CTLA-4) in combination with RT and a separate Phase 2 study of NIVO/IPI + RT in metastatic colorectal cancer showed durable activity with patients experiencing benefit outside the local radiation field and similar toxicities to those on dual ICI therapy alone.16,17
In melanoma specifically, a recent Phase I study of NIVO/IPI + RT in advanced melanoma patients was pursued to address the safety of this combination.10 Two dosing schedules were used. Both used standard NIVO 1mg/kg and IPI 3mg/kg every 21 days, while Cohort A received extracranial RT with a dose of 30 Gy in 10 fractions and Cohort B received 27 Gy in 3 fractions. Patients responded to treatment outside of the irradiated volume (Cohort A 5/10; Cohort B 1/9). No patients had progression of irradiated metastases. Safety profile showed no marked difference between SOC NIVO/IPI and NIVO/IPI + RT and RT did not compromise the ability of patients to receive intended combination immunotherapy.10 Sample size was too small to address questions of improved efficacy.
Because there have been few studies in this arena, the best treatment regimen including optimum dose and schedule is not known. We do know that the effects of RT are dose dependent, and the manner in which the total RT dose is fractionated may be of immunologic clinical relevance.18 More direct comparison studies of various RT regimens and outcomes would be beneficial. Our patients received the same novel dosing schedule for NIVO/IPI + RT which included a total of 40Gy in 10 fractions given by a split course of 5 fractions each delivered concurrently with 2 dual-ICI infusions 21 days apart. Given the relative radioresistance of melanoma, a high total RT dose with a dose per fraction size of 8–9 Gy is typically used for melanoma metastases.10 The dramatic and fairly rapid response we saw in these two cases with extensive disease burden treatment is likely to be the result of immunomodulation caused by the combination therapy rather than RT alone. Also, consistent with other reports, RT/ICI provided excellent/prolonged disease control within the RT field for our 2 cases.
There are currently no reliable biomarkers to help identify patients that may benefit from this combination therapy or to help trend clinical benefit with therapy. Current small sample sizes do not allow proper statistical analysis for associations between immune correlates and clinical outcomes and instead are preliminary and descriptive. In the advanced melanoma Phase 1 NIVO/IPI + RT study they noted that responders generally seemed to have increases in TCR diversity and saw increases in the proportion of Ki67 + PD1 + CD8 T cells and Ki67 + CD4 + T cells with the combination treatment.10
One known subset of therapy-responsive effector CD8 + T cells express the chemokine receptor CX3CR1. These T cells have the ability to withstand chemotherapy toxicity and are increased in patients with metastatic melanoma who respond to combination chemoimmunotherapy.19,20 Clinical models suggest that these CX3CR1 + CD8 + T cells are PD-1 therapy–responsive effector CD8 + T cells capable of entering tumor tissues and exhibiting anti-tumor effects.19 We also know CX3CR1 + CD8 + T cells increase after effective combined CIT and we wondered if we would see changes in the setting of NIVO/IPI + RT. We collected CX3CR1 + CD8 + T cell measurements for Mr. E prior to, during and after radiation (Fig. 2). Consistent with the low CX3CR1 + T cells seen in patients who failed to respond to CIT in our previous study, CX3CR1 + CD8 + T cell level was low prior to RT when Mr. E experienced significant disease progression with CIT. This T cell subset increased concurrent to RT + ICI when he clearly experienced significant anti-tumor benefit. The subsequent decrease of CX3CR1 + CD8 + T cell seen after NIVO/IPI + RT completion is likely due to the tissue migration of this effector T cell subset. Although additional studies in future prospective trials is needed, our results suggest that CX3CR1 + CD8 + T cell measurement, which can be obtained with simple peripheral blood draw, could be a used as a potential biomarker for response monitoring in these patients and guide the design of rational ICI/RT combination strategy.
Although radiotherapy and immune checkpoint inhibition is not a novel approach, we are continuing to learn more about how triple therapy (RT + anti-CTLA-4 + anti-PD-1/PD-L1) affects both the tumor microenvironment and the systemic tumor burden. Recall that both patients failed multiple lines of systemic therapy, including CIT, and responded to subsequent RT + ICI. For these heavily pre-treated patients with extensive disease burden that is not suitable for a traditional RT regimen, we were able to alleviate significant side effects and avoid the debility of surgery using our triple combination regimen with novel RT planning. Our patients did very well with their regimen. Neither patient developed grade 3 or above toxicities from the combination strategy including Mr. B who was fairly high risk for complications given his other comorbidities. Neither patient developed significant cytopenias given the lack of radiated bone marrow areas.
Although our treatment strategy needs to be validated in a prospective study, given the response and safety we observed here, this can be used as a potentially safe approach, especially in cases that a typical RT approach is not feasible and patients are not eligible for trials.