Augmented Transgenic TCR-mediated tumor therapy

University Of Washington, Seattle WA

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Abstract

Project Summary/Abstract Augmented transgenic T cell receptor therapy for virus positive Merkel cell Carcinoma Merkel cell carcinoma (MCC) is a highly aggressive and lethal skin cancer. The Merkel cell polyomavirus (MCPyV) is clonally integrated in ~80% of MCC tumors, which require continuous expression of the MCPyV T-Antigen (T-Ag) oncoproteins. As targeting these virus-specific proteins is unlikely to cause auto-immune complications, MCPyV- driven MCC tumors are ideal immunogenic targets for cell-mediated immune responses. Indeed, T cell activation folllowing immune checkpoint inhibitor (CPI) therapy can induce durable responses, but >50% of patients do not fully benefit from available CPIs, highlighting an unmet clinical need for more effective treatment strategies. In the previous P01 grant cycle, we identified a highly avid HLA Class I-restricted T cell receptor (TCR) targeting an HLA A*0201-presented MCPyV common T-Ag epitope (“TCRMCC1”), which can recognize the HLA-presented T-Ag epitope. Prior to infusion of TCRMCC1 (TTCR-MCC1)-transduced CD4 and CD8 T cells, efforts were made to counter HLA Class I downregulation common in MCC. These included single fraction radiation (SFRT) to non-index lesions, pro- inflammatory systemic lymphodepleting chemotherapy (LDC), or exogenous IFNγ1b (Actimmune®), with the latter identified from our screens as the most efficient compound for upregulating HLA Class I in vitro. Two of seven participants exhibited measurable responses. One who had received preceding radiation experienced regression of 13/14 skin lesions and one who had received systemic IFNγ1b exhibited, after initial progression, regression of all lesions. TTCR-MCC1 were detectable in the peripheral blood and preferentially localized to the tumor. Deep analysis of non-responding/escape and regressing lesions revealed CD8 more than CD4 TTCR-MCC1 preferentially localized to tumor suggesting the CD4-associated TCR engagement may not be sufficient to maintain them at the tumor site, and transcriptional HLA Class I downregulation (as opposed to genetic deletion) closely correlated with progression/escape. Additionally, we observed cytokine-producing T cells in vivo in participants could reverse MCC HLA downregulation in situ and lead to tumor regression better than other systemic or local radiation interventions. To more efficiently engage CD4 T cells towards targets with limited HLA/T-Ag presentation, we added CD8αβ to the engineering vector. As the CD200 membrane glycoprotein promotes immune evasion and is expressed in >85% of MCCs, we added a sequence to encode a CD200R/CD28 immunomodulatory fusion protein (IFP) in our engineering vector. In pre-clinical studies, these enhanced “(e)TTCR-MCC1” promoted T cell proliferation, function, survival, triggered MCC-specific HLA Class I upregulation and eliminated established MCC cell lines in NSG mice. We now plan to assess in a proof-of-principle clinical trial whether this improved vector can improve efficacy (Aims 1 & 2). Because MCC can evade immune responses, we also plan to explore additional intrinsic IFP modifications in murine/human tumor models, to inform future clinical strategies (Aim 3).