Genetic redirection of T lymphocytes with chimeric antigen receptors (CARs) has soared from treating cancers preclinically to FDA approval for hematologic malignancies and commercial-grade production scale in under 30 years. To date, solid tumors are less susceptible to CAR therapies and instead have been treated more successfully with immune checkpoint blockade or tumor-infiltrating lymphocyte therapy. Here, we discuss the current challenges in treating solid tumors with CAR T cells, and the obstacles within the host and tumor microenvironment hindering their efficacy. We present a novel three-pronged approach for enhancing the efficacy of CAR T cells whereby a single infusion product can synergize the power of an optimal CAR construct, a highly potent T cell subset, and rejuvenate the endogenous immune response to conquer therapeutically-resistant solid tumors.

Oral cavity squamous cell carcinoma (OCSCC) is a prevalent surgically treated subset of head and neck cancer with frequent recurrence and poor survival. Immunotherapy has demonstrated efficacy in recurrent/metastatic head and neck cancer. However, whether antitumor responses could be fostered by neoadjuvant presurgical immunotherapy remains unclear. Using a Simon’s two-stage design, we present results of a single-arm phase-II trial where 12 patients with stage II-IVA OCSCC received 3 to 4 biweekly doses of 3 mg/kg nivolumab followed by definitive surgical resection with curative intent. Presurgical nivolumab therapy in this cohort shows an overall response rate of 33% (n = 4 patients; 95% CI: 12%–53%). With a median follow up of 2.23 years, 10 out of 12 treated patients remain alive. Neoadjuvant nivolumab is safe, well-tolerated, and is not associated with delays in definitive surgical treatment in this study. This work demonstrates feasibility and safety for incorporation of nivolumab in the neoadjuvant setting for OCSCC (ClinicalTrials.gov: NCT03021993).

Human CD4 ⁺ T cell subsets elicit differential immunity against solid tumors when redirected with antigen specificity.

This study aimed to enhance antitumor immune responses to pancreatic cancer via Ab-based blockade of IL-6 and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4). Mice bearing s.c. or orthotopic pancreatic tumors were treated with blocking Abs to IL‑6 and/or CTLA-4. In both tumor models, dual IL-6 and CTLA-4 blockade significantly inhibited tumor growth. Additional investigations revealed that dual therapy induced an overwhelming infiltration of T cells into the tumor as well as changes in CD4 ⁺ T cell subsets. Dual blockade therapy elicited CD4 ⁺ T cells to secrete increased IFN-γ in vitro. Likewise, in vitro stimulation of pancreatic tumor cells with IFN-γ profoundly increased tumor cell production of CXCR3-specific chemokines, even in the presence of IL-6. In vivo blockade of CXCR3 prevented orthotopic tumor regression in the presence of the combination treatment, demonstrating a dependence on the CXCR3 axis for antitumor efficacy. Both CD4 ⁺ and CD8 ⁺ T cells were required for the antitumor activity of this combination therapy, as their in vivo depletion via Abs impaired outcomes. These data represent the first report to our knowledge of IL-6 and CTLA‑4 blockade as a means to regress pancreatic tumors with defined operative mechanisms of efficacy.

The accessibility of adoptive T-cell transfer therapies (ACT) is hindered by the cost and time required for product development. Here we describe a streamlined ACT protocol using Th17 cells expanded only 4 days ex vivo. While shortening expansion compromised cell yield, this method licensed Th17 cells to eradicate large tumors to a greater extent than cells expanded longer term. Day 4 Th17 cells engrafted, induced release of multiple cytokines including IL6, IL17, MCP-1, and GM-CSF in the tumor-bearing host, and persisted as memory cells. IL6 was a critical component for efficacy of these therapies via its promotion of long-term immunity and resistance to tumor relapse. Mechanistically, IL6 diminished engraftment of FoxP3+ donor T cells, corresponding with robust tumor infiltration by donor effector over regulatory cells for the Day 4 Th17 cell product relative to cell products expanded longer durations ex vivo. Collectively, this work describes a method to rapidly generate therapeutic T-cell products for ACT and implicates IL6 in promoting durable immunity of Th17 cells against large, established solid tumors. Significance: An abbreviated, 4-day ex vivo expansion method licenses Th17 cells to confer long-lived immunity against solid malignancies via induction of systemic IL6 in the host. See related commentary by Fiering and Ho, p. 3795