Journal for immunotherapy of cancer · 2026
Intrinsic tumor cell line immunogenicity may drive CAR-independent T cell responses and confound CAR T cell preclinical modeling.
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Sheng Michael K, Firoz Wahed A, Loi Kelly, Vick Logan V, Collins Craig P, Nielsen Ryan N, Schmeling Jessica L, Gulati Shuchi, Judge Sean J, Canter Robert J, Monjazeb Arta M, Zamora Anthony E, Murphy William J
Аннотация
BACKGROUND: Chimeric antigen receptor (CAR) T cells are highly potent therapies approved by the U.S. Food and Drug Administration (FDA) for several hematological malignancies. However, efficacy remains variable due to resistance, antigen modulation, systemic toxicities, and relapse. Developing improved CAR T cell therapies relies on preclinical models that accurately predict clinical outcomes. For this purpose, immortalized tumor cell lines, such as the Burkitt's lymphoma line Raji, are commonly used.
METHODS: CD19-targeting CAR (CAR19) and non-transduced (NT) human T cells were co-cultured with target cell lines in vitro to assess T cell cytotoxicity, cytokine production, activation, and proliferation. Major histocompatibility complex (MHC) class I and II blocking antibodies and TCR knockout (KO) T cells were used to validate T cell receptor interactions. In vivo, Raji wild-type (wt) or CD19 KO tumor-bearing mice were treated with CAR19 or NT T cells, and survival, tumor burden, serum cytokines, and T cell phenotype in tissues were analyzed. Statistical analyses using either paired/paired ratio/unpaired two-tailed Student's t tests, two-way analysis of variance, and log-rank (Mantel-Cox) tests were performed using GraphPad Prism 9.
RESULTS: We report that T cells generated from multiple different donors exhibit not only strong CAR-mediated cytotoxicity against CD19-expressing Raji WT cells but also, unexpectedly, CAR-independent reactivity against Raji CD19 KO cells. This reactivity was observed both in vitro and in vivo, and was associated with pro-inflammatory cytokine secretion and upregulation of T cell activation markers, consistent with endogenous T cell receptor (TCR) engagement. NT T cells displayed similar activation, cytotoxic, and cytokine responses against Raji cells. These effects failed to occur using other B cell leukemia/lymphoma or solid tumor cell lines in vitro. Both CD4+ and CD8+ T cell populations contributed to this alloreactive response, which could be attenuated by blockade of MHC class I or II, highlighting a TCR:MHC-dependent mechanism.
CONCLUSIONS: These findings demonstrate that certain tumor lines can elicit strong allogeneic T cell responses independent of CAR specificity, revealing an important limitation of commonly used preclinical models and highlighting the potential for false-positive assessments of CAR T cell efficacy. Furthermore, these results highlight the importance of validating tumor models for alloreactivity prior to use in preclinical testing.
METHODS: CD19-targeting CAR (CAR19) and non-transduced (NT) human T cells were co-cultured with target cell lines in vitro to assess T cell cytotoxicity, cytokine production, activation, and proliferation. Major histocompatibility complex (MHC) class I and II blocking antibodies and TCR knockout (KO) T cells were used to validate T cell receptor interactions. In vivo, Raji wild-type (wt) or CD19 KO tumor-bearing mice were treated with CAR19 or NT T cells, and survival, tumor burden, serum cytokines, and T cell phenotype in tissues were analyzed. Statistical analyses using either paired/paired ratio/unpaired two-tailed Student's t tests, two-way analysis of variance, and log-rank (Mantel-Cox) tests were performed using GraphPad Prism 9.
RESULTS: We report that T cells generated from multiple different donors exhibit not only strong CAR-mediated cytotoxicity against CD19-expressing Raji WT cells but also, unexpectedly, CAR-independent reactivity against Raji CD19 KO cells. This reactivity was observed both in vitro and in vivo, and was associated with pro-inflammatory cytokine secretion and upregulation of T cell activation markers, consistent with endogenous T cell receptor (TCR) engagement. NT T cells displayed similar activation, cytotoxic, and cytokine responses against Raji cells. These effects failed to occur using other B cell leukemia/lymphoma or solid tumor cell lines in vitro. Both CD4+ and CD8+ T cell populations contributed to this alloreactive response, which could be attenuated by blockade of MHC class I or II, highlighting a TCR:MHC-dependent mechanism.
CONCLUSIONS: These findings demonstrate that certain tumor lines can elicit strong allogeneic T cell responses independent of CAR specificity, revealing an important limitation of commonly used preclinical models and highlighting the potential for false-positive assessments of CAR T cell efficacy. Furthermore, these results highlight the importance of validating tumor models for alloreactivity prior to use in preclinical testing.