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Reovirus type 3 Dearing (Reo), manufactured for clinical application as pelareorep, is an attractive anticancer agent under evaluation in multiple phase 2 clinical trials for the treatment of solid tumors. It elicits its anticancer efficacy by inducing both oncolysis and intratumoral T-cell influx. Because most people have been preexposed to Reo, neutralizing antibodies (NAb) are prevalent in patients with cancer and might present a barrier to effective Reo therapy. Here, we tested serum of patients with cancer and healthy controls (n = 100) and confirmed that Reo NAbs are present in >80% of individuals. To investigate the effect of NAbs on both the oncolytic and the immunostimulatory efficacy of Reo, we established an experimental mouse model with Reo preexposure. The presence of preexposure-induced NAbs reduced Reo tumor infection and prevented Reo-mediated control of tumor growth after intratumoral Reo administration. In B cell-deficient mice, the lack of NAbs provided enhanced tumor growth control after Reo monotherapy, indicating that NAbs limit the oncolytic capacity of Reo. In immunocompetent mice, intratumoral T-cell influx was not affected by the presence of preexposure-induced NAbs and consequently, combinatorial immunotherapy strategies comprising Reo and T-cell engagers or checkpoint inhibitors remained effective in these settings, also after a clinically applied regimen of multiple intravenous pelareorep administrations. Altogether, our data indicate that NAbs hamper the oncolytic efficacy of Reo, but not its immunotherapeutic capacity. Given the high prevalence of seropositivity for Reo in patients with cancer, our data strongly advocate for the application of Reo as part of T cell-based immunotherapeutic strategies., (©2024 The Authors; Published by the American Association for Cancer Research.)

The accumulation of tumor-specific CD4 + and CD8 + effector T cells is key to an effective antitumor response. Locally, CD4 + T cells promote the recruitment and effector function of tumor-specific CD8 + T cells and activate innate killer cells in the tumor. Here, we show that tumor-specific CD4 + T cells were predominantly present in the CD39 + subset of tumor-infiltrating lymphocytes (TIL). The CD39 + CD4 + and CD8 + TILs were detected in three different tumor types, and displayed an activated (PD-1 + , HLA-DR + ) effector memory phenotype. CD4 + CD39 + single-cell RNA-sequenced TILs shared similar well-known activation, tissue residency, and effector cell-associated genes with CD8 + CD39 + CD103 + TILs. Finally, analysis of directly ex vivo cell-sorted and in vitro expanded pure populations of CD39-positive and negative CD4 + and CD8 + TILs revealed that tumor-specific antigen reactivity was almost exclusively detected among CD39 + cells. Immunotherapy of cancer is based on the activation of tumor-reactive CD4 + and CD8 + T cells. We show that the expression of CD39 can be used to identify, isolate, and expand tumor-reactive T-cell populations in cancers., (©2020 American Association for Cancer Research.)