JITC Digest April 2022

JITC Editor Picks

Engineering adoptive T cell therapy to co-opt Fas ligand-mediated death signaling in ovarian cancer enhances therapeutic efficacy

Journal for ImmunoTherapy of Cancer 2022;9:e003959 (9 March 2022)
Research

Summary:

Immune suppression in the tumor microenvironment is a major obstacle limiting the success of chimeric antigen receptor (CAR) T cell approaches for solid tumors. Reasoning that Fas/FasL signaling in the ovarian cancer tumor microenvironment may limit the persistence and antitumor activity of CAR T cells, Kristin G Anderson and colleagues generated a fusion protein containing the Fas extracellular binding domain fused to a 4-1BB co-stimulatory domain instead of the endogenous death domain. Mesothelin-specific CAR T cells co-transduced with the fusion protein had lower levels of apoptosis by cleaved caspase 3, increased proliferation by Ki67, and higher IL-2 production compared to the parental lines in vitro when co-cultured with FasL-expressing tumor or T cells. In murine models, the CAR T cells expressing the fusion protein had enhanced proliferation, survival, and IL-2 production, which was associated with prolonged median survival. Analysis of samples from human patients with ovarian cancer demonstrated high levels of FasL expression in primary and metastatic tumors. In coculture experiments with human T cells and human ovarian cancer cell lines, cotransduction with the fusion protein and a mesothelin-specific T cell receptor (TCR) led to greater viability and equivalent cytotoxicity compared to TCR-transduced T cells. The results offer a strategy to enhance the efficacy of adoptive cell therapies by co-opting apoptotic signals in the microenvironment to support proliferation of engineered T cells.

Novel imaging biomarkers predict outcomes in stage III unresectable non-small cell lung cancer treated with chemoradiation and durvalumab

Research

Summary:

Consolidation therapy with the anti-PD-L1 durvalumab after chemoradiation is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC), but response rates are less than 30% and robust biomarkers to predict clinical benefit are lacking. Hypothesizing that subvisual features of pre-treatment NSCLC tumors on CT imaging may correspond to physiologic characteristics that increase likelihood of recurrence, Khalid Jazieh and colleagues developed a radiomic risk score to predict progression free survival (PFS) and overall survival (OS) after durvalumab consolidation. In training and validation sets that each included 59 patients with unresectable stage III NSCLC who received durvalumab consolidation, low pre-treatment radiographic risk scores were associated with significantly improved PFS and OS. High radiomic risk score was also associated with worse PFS and OS in a separate cohort of 15 patients that received chemoradiotherapy alone. High radiographic risk score was associated with worse PFS regardless of tumor PD-L1 expression status. For OS, however, a low radiographic risk score only corresponded with improved survival outcomes in the patients with tumor PD-L1 expression less than 50%. Decision curve analysis demonstrated that an integrated radiomic risk score and clinical model had the highest net benefit in identifying patients who should receive consolidation durvalumab. With further validation, CT image-derived radiomic biomarkers may provide a minimally invasive decision support tool for consideration of risks versus benefits of immunotherapy.

1alpha,25(OH)₂D₃ reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells

Peng Li, Xinhai Zhu, Guangchao Cao, Ruan Wu, Ke Li, Wenhui Yuan, Biyun Chen, Guodong Sun, Xichun Xia, Hua Zhang, Xiao Wang, Zhinan Yin, Ligong Lu, Yunfei Gao
Journal for ImmunoTherapy of Cancer 2022;9:e003477 (22 March 2022)
Research

Summary:

Vitamin D deficiency is associated with increased risk of prostate, lung, breast, and liver cancer. Peng Li and colleagues provide preclinical and early clinical data demonstrating that an active metabolite of vitamin D modulates expression of exhaustion markers and enhances cytotoxicity in CD8⁺ and Vgamma9Vdelta2⁺ T cells. In a clinical trial that included 53 patients with advanced non-small cell lung cancer (NSCLC) and 47 healthy controls, serum levels of the vitamin D metabolite 1alpha,25(OH)₂D₃ (calcitriol) were inversely correlated with expression of PD-1, TIGIT, and TIM-3 on cytotoxic T cells. Oral supplementation with calcitriol decreased expression of PD-1, TIGIT and TIM-3 on CD8⁺ and Vgamma9Vdelta2⁺ T cells with a concomitant increase in CD28 in NSCLC patients treated with docetaxel. In vitro, the vitamin D receptor (VDR) was required for the changes in surface exhaustion and activation marker expression with calcitriol and ChiP-seq demonstrated VDR binding in the promoter regions of the Pdcd1, Tigit, Tim3, and Cd28 loci. The interaction of VDR with the promoters of Pdcd1 and Cd28 was differentially affected by DNA methyltransferase inhibition and histone deacetylation. Knockout of VDR attenuated calcium ion influx upon T cell receptor engagement in Vgamma9Vdelta2⁺ T cells, resulting in reduced interferon gamma and tumor necrosis factor alpha production. Pre-treatment with calcitriol enhanced cytotoxicity in Vgamma9Vdelta2⁺ T cells in vitro and enhanced tumor control in adoptive transfer experiments with no off-target damage detected to organs, including the liver, kidneys, and lungs. The preclinical and early clinical evidence combined with the well-characterized safety of vitamin D provide compelling rationale for the investigation of VDR-targeted combination approaches to enhance anti-tumor immunity.

MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer

Summary:

Despite a well-characterized role for alterations in the mitogen-activated protein kinase (MAPK) pathway in the pathogenesis of head and neck cancer, MEK inhibition has not demonstrated clinical benefit in these patients. Manu Prasad and colleagues reveal a new mechanism by which MEK inhibition transiently sensitizes MAPK-driven head and neck tumors to anti-PD-1 followed by re-establishment of an immunosuppressive microenvironment. In multiple murine MAPK-driven head and neck cancer models, CD8⁺ T cells were required for tumor growth inhibition with the MEK inhibitor trametinib. T cells isolated from trametinib-treated tumors expressed high levels of interferon gamma, were highly proliferative, and had low expression of the exhaustion markers TIM-3 and PD-1. In vivo, 5 days of trametinib treatment prior to anti-PD-1 led to complete tumor regression and rejection upon rechallenge whereas resistance after a short-lived delay in tumor growth was observed for either monotherapy. Short-term trametinib exposure was associated with a reduction in tumor-derived CSF-1, and a concomitant decrease in M2-like macrophages and monocytic dendritic cell-like myeloid-derived suppressor cells. Enforced overexpression of CSF-1 in tumor cells dramatically reduced the anti-tumor efficacy of trametinib followed by anti-PD1. Notably, prolonged exposure to trametinib (ie, 25 days) prior to anti-PD-1 did not lead to tumor rejection and after 25 days of treatment, CD8⁺ T cell infiltration was comparable to those isolated from vehicle-treated mice. The findings highlight the dynamic evolution of the immune microenvironment in head and neck cancer, providing rationale for the investigation of transient priming strategies for combination targeted and immunotherapy regimens.

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