Neoadjuvant SEMA4D/ICB therapy for melanoma - ABSTRACT This MPI R01 proposal seeks to advance our understanding of how a novel neoadjuvant therapy impacts the immune system in patients with solid tumors, using refractory melanoma as a model. This work stems from a series of discoveries by our team, led by basic T cell immunologist (Dr. Paulos) and translational scientist (Dr. Lesinski) in the context of a neoadjuvant, window of opportunity clinical trial (NCT03769155) in patients with resectable metastatic melanoma. These patients were treated with a novel agent called pepinemab—an antibody that blocks semaphorin 4D (SEMA4D) signaling—in combination with nivolumab and/or ipilimumab—as a ‘neoadjuvant’ presurgical therapy only being conducted at our institution (Winship/Emory). We found that most patients (7/8) given pepinemab/nivolumab/ipilimumab have not recurred after treatment nearly 4 years later (ongoing response). Our data reveals that type I conventional dendritic cells (cDC1) and M1 macrophages were increased in tumors of patients given potent αSEMA4D-based combination therapy, suggesting they play a key role as antigen presenting cells. Also, B cells and CD4+ T cells infiltrated tumors of patients treated with αSEMA4D/immune checkpoint blockade (ICB), versus those receiving standard of care nivolumab or surgery alone. Our teams’ results suggest SEMA4D blockade and ICB strengthens cDC1 and M1 macrophage induction in the tumor. This in turn enhances B-T cell interactions that drive adaptive immune responses and can safely elicit efficacy in melanoma, overcoming αPD-1 resistance. In Aim 1, using unique surgical tissue specimens from this trial, we will gain insight in how blocking SEMA4D impacts cDC1 and macrophages, positing their infiltration into the tumor is enhanced when combined with ICB, along with increased proximity of B cells to stem-like T cells in tumor specimens. These data will be compared to that from surgical samples of patients given neoadjuvant nivolumab/ipilimumab (from Co-I Dr. Wargo) to test our idea that αSEMA4D uniquely acts on myeloid cells to impart ICB treatment efficacy. In Aim 2, using genetically diverse murine neoadjuvant models, we will mirror our clinical trial and explore the role of distinct immune cell populations including B cells, T cells, cDC1 and macrophages in eliciting durable immunity via antibody depletion or using conditional knockout mice. Finally, our work reveals the inhibitory checkpoint LAG3 is induced on TIL of patients unresponsive to αSEMA4D/PD-1 therapy and is induced in mice by this therapy. In Aim 3, we will use relevant mouse models to determine if LAG3 blockade can serve as a more tolerable and efficacious alternative to αCTLA-4 that can be targeted to overcome αSEMA4D/PD-1 resistance, in turn mediating primary and protective immune responses against tumors. Overall, the proposed research will uncover the mechanism by which αSEMA4D-containing regimens sustain durable immunity against advanced melanoma and how this target can pair with LAG3 ICB for future clinical translation. This work will have impact across solid tumors as a future approach to rescue patients nonresponsive to emerging systemic immunotherapies.
