PD-1-directed immune checkpoint inhibitors (ICI) have significantly improved survival in metastatic melanoma compared to traditional chemotherapy. Unfortunately, less than half of patients with melanoma respond to ICI treatment. Anti-PD1/PD-L1 ICI resistance extends beyond melanomas, resulting in a meager 15-35% response rate for most cancers. Melanomas secrete factors that lead to ICI resistance, including soluble PD-L1 (sPD-L1) and PD-L1-positive extracellular vesicles (evPD-L1). We recently discovered that both sPD-L1 and evPD-L1 in the peripheral blood directly kill effector CD8+ T cells through interaction with the PD-1 receptor (Fig 4). They also indirectly ?quench? the available therapeutic anti-PD-1 antibody resulting in low ICI response rates (Fig 5). Thus, there is an urgent need to remove these soluble forms from circulation to rescue patients with melanoma from ICI resistance. We have previously shown that stereotactic body radiotherapy (SBRT) can improve systemic immune responses, known as ?abscopal effect.? Abscopal effect is the result of SBRT inducing neoantigens, pro- inflammatory cytokines, and up-regulating major histocompatibility complex and B7 family co-stimulatory molecules on antigen presenting cells to recruit effector T cells. Unfortunately, abscopal effect is rarely observed in patient, and therefore, ICI and radiotherapy combination studies are ongoing. While SBRT activates anti- melanoma immunity by providing neoantigens and danger signals, tumors release these immunosuppressive extracellular forms of PD-L1 that kill activated effector T cells (Fig 1). Radiotherapy increases tumor sPD- L1/evPD-L1 release, and we have reported that high plasma sPD-L1 and/or evPD-L1 levels portend poor response to therapy and survival. Recently, we have discovered that therapeutic plasma exchange (TPE), a safe and commonly performed procedure for other medical indications (e.g. autoimmune diseases, myasthenia gravis, multiple sclerosis, etc), removes both sPD-L1 and evPD-L1 safely from the circulation. Therefore, we hypothesize that the removal of circulating sPD-L1 and evPD-L1 by TPE may overcome PD-L1/PD-1-mediated immune regulation to improve ICI + SBRT response rates and survival in patients with metastatic melanoma. If successful, our proposed concept can be readily investigated in a prospective randomized clinical trial and involve many centers that routinely perform TPE. Furthermore, our novel concept can be explored in other cancer histologies with PD- L1/PD-1 resistance where elevated sPD-L1 and evPD-L1 are detected in patients? blood. Figure 1: Extracellular forms of PD-L1 (1) evPD-L1 and (2) sPD-L1 cause resistance to PD-(L)1 inhibitor therapy in cancer by outcompeting PD-(L)1 inhibitors and killing CD8+ effector T cells (see also Figure 4). The availability of therapeutic anti-PD-L1 inhibitors is ?quenched? by soluble PD-L1 and evPD-L1 released from tumor cells which limits its availability. Furthermore, sPD-L1 and evPD-L1 can bind to T cell surface PD-1 receptors and outcompete anti-PD-1 inhibitors. Radiotherapy Tumor Cell 1 PD-L1+ EVs PD1 Immune Cell PD-L1-Inhibitor ADAM10/ ADAM17 2 PD-L1sPD-L1 PD-1-Inhibitor PD1

Public Health Relevance

Gold standard clinical trials in metastatic melanoma have demonstrated significantly improved survival with immunotherapy (e.g. immune checkpoint inhibitors; anti-PD1 and anti-PD-L1). However, only about 35% of all patients benefit and almost all patients eventually develop resistance to immunotherapy and succumb to their cancer. Stereotactic body radiotherapy is a highly advantageous treatment modality in melanoma due to its ability to overcome radioresistance and allow patients to mount an immune response against melanoma that can synergize with immunotherapy, also known as the abscopal effect. Despite these advanced therapies, melanomas develop resistance by releasing immunosuppressive molecules (sPD-L1 and evPD-L1) in the blood that kill activated immune cells directed against melanoma. Therefore, we propose to incorporate therapeutic plasma exchange (a safe and commonly used therapy in patients with autoimmune disease) to remove immunosuppressive molecules and overcome melanoma therapy resistance and rescue anti- melanoma immunity brought by radiotherapy and immunotherapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1)
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Song, Min-Kyung H
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Mayo Clinic, Rochester
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