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Cancer immunotherapy such as anti-PD-1/anti-PD-L1 immune checkpoint blockade (ICB) can provide significant clinical benefit in patients with advanced malignancies. However, most patients eventually develop progressive disease, thus necessitating additional therapeutic options. We have developed a novel agent, a-TEA-LS, that selectively induces tumor cell death while sparing healthy tissues, leading to increased activation of tumor-reactive T cells and tumor regression. In the current study, we explored the impact of combined a-TEA-LS + ICB in orthotopic and spontaneously arising murine models of mammary carcinoma. We found that a-TEA-LS + ICB led to increased production of pro-inflammatory cytokines that were associated with a reduction in tumor growth and prolonged survival. Together, these data demonstrate the potential utility of a-TEA-LS + ICB for the treatment of breast cancer and provide the rationale for clinical translation of this novel approach., Competing Interests: Author EA was employed by and has ownership interest in Veana Therapeutics. WR: Research support from Bristol-Myers Squibb, GlaxoSmithKline, MiNA Therapeutics, Inhibrx, Veana Therapeutics, Shimadzu, OncoSec, Galecto, Turn Bio, CanWell Pharma, and Calibr. Patents/Licensing fees: Galectin Therapeutics. Scientific Advisory Boards: Vesselon, Medicenna, Veana Therapeutics. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Redmond, Kasiewicz and Akporiaye.)

Metaplastic breast cancer is a rare and often chemo-refractory subtype of breast cancer with poor prognosis and limited treatment options. Recent studies have reported overexpression of programmed death ligand 1 (PD-L1) in metaplastic breast cancers, and there are several reports of anti-PD-1/L1 being potentially active in this disease. In this case series, we present 5 patients with metastatic metaplastic breast cancer treated with anti-PD-1-based therapy at a single center, with 3 of 5 cases demonstrating a response to therapy, and one of the responding cases being a metaplastic lobular carcinoma with low-level hormone receptor expression. Cases were evaluated for PD-L1 expression, tumor infiltrating lymphocytes (TILs), DNA mutations, RNA sequencing, and T-cell receptor sequencing. Duration of the response in these cases was limited, in contrast to the more durable responses noted in other recently published reports., Competing Interests: WR: Research support from Galectin Therapeutics, Bristol Myers Squibb (BMS), Merck, Tesaro/GlaxoSmithKline, MiNA Therapeutics, Inhibrx, Veana Therapeutics, Aeglea Biotherapeutics, Shimadzu, OncoSec, and Calibr. Patents/Royalties: Galectin Therapeutics. Advisory Boards: Nektar Therapeutics, Vesselon. DP: Received advisory board honoraria and institutional research funding support from Brooklyn ImmunoTherapeutics, Bristol-Myers Squibb, and Merck Laboratories. DP receives speaker bureau honoraria from Genentech and Novartis. Unrelated to this work, DP has received additional advisory board honoraria from other entities. RB: Consulting fees: Genomic Health, Astra Zeneca, Genentech; Institutional research funding: Seattle Genetics, Ichnos Biosciences, Merck; Honoraria for speakers bureau: Genentech, Seattle Genetics. HM: Consulting or Advisory Role - AstraZeneca; Bristol-Myers Squibb; Daiichi Sankyo; Genentech; Genomic Health; Immunomedics; Lilly; Merck; Pfizer; Puma Biotechnology; Puma Biotechnology; Seattle Genetics, Research Funding - Bristol-Myers Squibb (Inst); Lilly (Inst); Merck, (Inst); ZIOPHARM Oncology (Inst), Travel, Accommodations, Expenses - Amgen; AstraZeneca; Bristol-Myers Squibb; DAVA Pharmaceuticals; Genentech; Immunomedics; Lilly; Merck; Pfizer; Puma Biotechnology; Spectrum Pharmaceuticals, Other Relationship - Genomic Health; Lilly. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kim, Rajamanickam, Bernard, Chun, Wu, Martel, Sun, Redmond, Sanchez, Basho, McArthur and Page.)

Recent studies have highlighted the therapeutic efficacy of immunotherapy, a class of cancer treatments that utilize the patient's own immune system to destroy cancerous cells. Within a tumor the presence of a family of negative regulatory molecules, collectively known as "checkpoint inhibitors," can inhibit T cell function to suppress anti-tumor immunity. Checkpoint inhibitors, such as CTLA-4 and PD-1, attenuate T cell proliferation and cytokine production. Targeted blockade of CTLA-4 or PD-1 with antagonist monoclonal antibodies (mAbs) releases the "brakes" on T cells to boost anti-tumor immunity. Generating optimal "killer" CD8 T cell responses also requires T cell receptor activation plus co-stimulation, which can be provided through ligation of tumor necrosis factor receptor family members, including OX40 (CD134) and 4-1BB (CD137). OX40 is of particular interest as treatment with an activating (agonist) anti-OX40 mAb augments T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity against a variety of tumors. When used as single agents, these drugs can induce potent clinical and immunologic responses in patients with metastatic disease. However, each of these agents only benefits a subset of patients, highlighting the critical need for more effective combinatorial therapeutic strategies. In this review, we will discuss our current understanding of the cellular and molecular mechanisms by which OX40 agonists synergize with checkpoint inhibitor blockade to augment T cell-mediated anti-tumor immunity and the potential opportunities for clinical translation of combinatorial immunotherapeutic strategies.