A Prospective Clinical Trial Combining Radiation Therapy With Systemic Immunotherapy in Metastatic Melanoma

Abstract

Purpose: Local radiation therapy (RT) combined with systemic anti-cytotoxic T-lymphocyte-associated protein-4 immunotherapy may enhance induction of systemic antimelanoma immune responses. The primary objective of the present trial was to assess the safety and efficacy of combining ipilimumab with RT in patients with stage IV melanoma. The secondary objectives included laboratory assessment of induction of antimelanoma immune responses.

Methods and materials: In our prospective clinical trial, 22 patients with stage IV melanoma were treated with palliative RT and ipilimumab for 4 cycles. RT to 1 to 2 disease sites was initiated within 5 days after starting ipilimumab. Patients had ≥1 nonirradiated metastasis measuring ≥1.5 cm available for response assessment. Tumor imaging studies were obtained at baseline, 2 to 4 weeks after cycle 4 of ipilimumab, and every 3 months until progression. Laboratory immune response parameters were measured before and during treatment.

Results: Combination therapy was well-tolerated without unexpected toxicities. Eleven patients (50.0%) experienced clinical benefit from therapy, including complete and partial responses and stable disease at median follow-up of 55 weeks. Three patients (27.3%) achieved an ongoing systemic complete response at a median follow-up of 55 weeks (range 32-65), and 3 (27.3%) had an initial partial response for a median of 40 weeks. Analysis of immune response data suggested a relationship between elevated CD8-activated T-cells and response.

Conclusion: This is the second prospective clinical trial of treatment of metastatic melanoma using the combination of RT and systemic immunotherapy and the first using this sequence of therapy. The results from the present trial demonstrate that a subset of patients may benefit from combination therapy, arguing for continued clinical investigation of the use of RT combined with immunotherapy, including programmed cell death 1 inhibitors, which might have the potential to be even more effective in combination with RT.

Figure 1. Waterfall plot of best response of non-irradiated lesions

* non-irradiated lesions only

Figure 2

Abscopal response in patient with complete response to combination therapy. This patient had extensive dermal disease outside the radiation field and achieved a complete response to therapy; depicted here is one example lesion.

Figure 3

Serum cytokines in melanoma patients treated with radiation and ipilimumab analyzed by Luminex (A) Heat map showing the expression of 63 cytokines in patients with progressive disease (PD) or complete response/partial response (CR/PR) following treatment, at baseline and 2nd and 4th doses of ipilimumab (visit 2 and 3, resp.). (B) Serum levels of (clockwise) MIP1α, IP-10, MIG and MIP1β. PD=Progressive Disease, CR/PR=Complete Response/Partial Response.

Figure 4

Intracellular cytokine staining and mass cytometric analyses of ex vivo stimulated PBMC from melanoma patients treated with radiation and ipilimumab (A) PBMC from melanoma patients receiving ipilimumab were collected and cryopreserved at baseline pre-treatment (visit 1), 2^nd ipilimumab dose (visit 2) and 4^th ipilimumab dose (visit 3). PBMC samples were rested and stimulated with PMA and Ionomycin for 4 hours, and then stained with the antibody panel shown in Table 1, and analyzed by CyTOF. IL-2 expression in CD8+ T cells is shown in A. PD and CR/PR groups were significantly different (p<0.01) (B) Mass cytometric analysis of samples from A revealed differences in CCR7+CD45RA− CD8+ T cells (central memory, Tcm). PD and CR/PR groups were found to be significantly different (p<0.05) (C-D) SPADE analysis of baseline IL-2 CyTOF data from one representative patient each for progressive disease and complete response. PD=Progressive Disease, CR/PR=Complete Response/Partial Response. *p<0.05.