Does Neutron Radiation Therapy Potentiate an Immune Response to Merkel Cell Carcinoma?

Abstract

Background: Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy. In the advanced setting, MCC is often treated with immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibodies. X-ray radiation therapy (XRT) is commonly used for palliation. There is an unmet need for new treatment options in patients progressing on immunotherapy and XRT. We present 2 patients with progressive MCC who were successfully treated with high linear energy transfer neutron radiation therapy (NRT). Clinical Observations: Patient A, an 85-year-old white male with chronic lymphocytic leukemia had progressive MCC with multiple tumors on the face despite prior XRT and ongoing treatment with pembrolizumab. The 5 most symptomatic lesions were treated with a short course of NRT (2 3 3 Gy) while continuing pembrolizumab. All irradiated facial lesions demonstrated a complete response 2 weeks after NRT. Remarkably, an additional 4 lesions located outside the NRT fields also completely resolved. Patient B, a 78-year-old white male with no immunosuppressive condition had recurrent MCC in the scalp and bilateral cervical nodes. The painful, ulcerative tumors on his scalp were progressing despite multiple courses of XRT and multiple immunotherapy regimens, including pembrolizumab. He was treated with NRT (16-18 Gy) to the scalp and had a complete response with successful palliation. While his disease subsequently progressed outside the NRT fields, the response to NRT bridged him to receive further investigational immunotherapies, and he remains disease free 3 years later. Conclusion: Short courses of high linear energy transfer particle therapy deserve consideration as a promising modality for local tumor control in XRT refractory tumors. The out-of-field response suggests that NRT has potential for synergizing with immunotherapy. While more data are required to identify optimal NRT parameters, the NRT dose that potentiates an antitumor immune response appears to be well below organ-at-risk tolerance.

A comparison of mechanism‐inspired models for particle relative biological effectiveness (RBE)

“…32,171,197 For example, there are some reports that high-LET radiations, such as carbon ions and fast neutrons, may be more effective at inducing antitumor immune activity than low-LET radiations. [198][199][200] However, the cellular and subcellular mechanisms of action embodied in the LEM IV, MK, and RMF models are still the most plausible explanations for the increased biological effectiveness of high-LET radiations relative to low-LET radiations (i.e., MV x rays) in the treatment of cancer (i.e., clinical endpoints).…”

“…There are also many potential cellular mechanisms of action beyond the ones considered in the LEM IV, MK, and RMF models, including bystander effects in vitro and in vivo, adaptive responses, immune therapy in combination with radiation, and tumor vasculature effects . For example, there are some reports that high‐LET radiations, such as carbon ions and fast neutrons, may be more effective at inducing antitumor immune activity than low‐LET radiations . However, the cellular and subcellular mechanisms of action embodied in the LEM IV, MK, and RMF models are still the most plausible explanations for the increased biological effectiveness of high‐LET radiations relative to low‐LET radiations (i.e., MV x rays) in the treatment of cancer (i.e., clinical endpoints).…”

Differential effects of high versus low linear energy transfer (LET) radiation on type-I interferon (IFNβ) and TREX1 responses

“…The results from this study are consistent with several clinical case studies of MCC patients treated with fast neutrons and add additional insight into potential clinical improvements in radiation delivery to enhance radiation-induced immunogenicity. Schaub et al 14 report on the treatment of an 85-year-old man with chronic lymphocytic leukemia having progressive MCC with multiple tumors on the face despite prior low-LET radiation therapy and ongoing treatment with anti-PD1 pembrolizumab. The five most symptomatic lesions interfering with the patient's vision were treated with two sequential neutron doses of 3 Gy separated by a few days while continuing pembrolizumab treatment.…”

“…The results from this study are consistent with several clinical case studies of MCC patients treated with fast neutrons and add additional insight into potential clinical improvements in radiation delivery to enhance radiation-induced immunogenicity. Schaub et al 14 report on the treatment of an 85-year-old man with chronic lymphocytic leukemia having progressive MCC with multiple tumors on the face despite prior low-LET radiation . CC-BY-NC-ND 4.0 International license available under a was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

“…9,10 Alternatively, a number of preclinical and clinical studies have indicated that high-LET radiation is highly immunogenic at lower doses, including studies with alpha particles, 11 carbon ions, 12,13 and fast neutrons. 14 For example, a recent case study observed an out-of-field (abscopal) response in a Merkel cell carcinoma (MCC) patient, previously refractory to low-LET radiation and PD-1 ICI with pembrolizumab, following high-LET fast neutron therapy (2 daily fractions of 3 Gy). 14 This case study highlights the potential of high-LET radiation to overcome metastatic disease that is non-responsive to low-LET radiation or immunotherapy alone.…”