Engineering T cells with chimeric antigen receptors (CARs) is an effective method for directing T cells to attack tumors, but may cause adverse side effects such as the potentially lethal cytokine release syndrome. Here the authors show that the T cell antigen coupler (TAC), a chimeric receptor that co-opts the endogenous TCR, induces more efficient anti-tumor responses and reduced toxicity when compared with past-generation CARs. TAC-engineered T cells induce robust and antigen-specific cytokine production and cytotoxicity in vitro, and strong anti-tumor activity in a variety of xenograft models including solid and liquid tumors. In a solid tumor model, TAC-T cells outperform CD28-based CAR-T cells with increased anti-tumor efficacy, reduced toxicity, and faster tumor infiltration. Intratumoral TAC-T cells are enriched for Ki-67+ CD8+ T cells, demonstrating local expansion. These results indicate that TAC-T cells may have a superior therapeutic index relative to CAR-T cells.

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The adoptive transfer of ex vivo--expanded T cells is a promising approach to treat several malignancies. Several lines of evidence support that the infusion of T cells with early memory features, capable of expanding and persisting after transfer, are associated with better outcomes. We report herein that exposure to exogenous TGFb during human T-cell stimulation ex vivo leads to the accumulation of early/central memory (Tcm) cells. Exposure to TGFb suppressed the expression of BLIMP-1, a key orchestrator of effector T-cell differentiation, and led to the upregulation of the memory-associated transcription factor ID3. Accordingly, this was associated with an early memory transcriptional signature in both CD4 þ and CD8 þ T-cell subsets. The T cells stimulated in the presence of TGFb expanded normally, and displayed polyfunctional features and no suppressive activity. The adoptive transfer of ex vivo--stimulated T cells into immunodeficient mice confirmed that TGFb-conditioned cells had an enhanced capacity to persist and mediate xenogeneic graft-versushost disease, as predicted by their early T-cell memory phenotype. Chimeric antigen receptor--expressing T cells generated in the presence of exogenous TGFb were cytotoxic and more effective at controlling tumor growth in immunodeficient animals. This work unveils a new role for TGFb in memory T-cell differentiation and indicates that TGFb signaling may be harnessed to program Tcm differentiation in the context of ex vivo T-cell stimulation for adoptive immunotherapy in humans.

FCRL4 is an immunoregulatory receptor expressed by a subpopulation of memory B cells. These tissue-based cells express increased levels of the src-family kinases HCK and FGR. In this study, we investigate the roles of these src-family kinases in FCRL4-mediated immunoregulation of B cells in the context of previously unrecognized palmitoylation of the receptor. We observed enhanced phosphorylation of FCRL4 on tyrosine residues in the presence of the HCK p59 or FGR. This phosphorylation was markedly reduced in assays using a palmitoylation-defective mutant of FCRL4. In reporter gene studies, we observe that FCRL4 expression enhances CpG-mediated activation of NF-κB signaling. Surprisingly, using a reporter gene linked to activation of the MAPK substrate Elk-1 in response to Ag receptor ligation, we find that FCRL4 has inhibitory activity in cells coexpressing FGR but an activating function in cells coexpressing HCK p59. We provide evidence that in primary memory B cells, expression of FCRL4 leads to increased expression of IL-10 in the presence of FGR or HCK p59 in response to CpG, but increased levels of IFN-γ only in the context of coexpression of FGR. Our study supports the specific requirement of HCK p59 and FGR src-family kinases for FCRL4-mediated immunomodulatory activity and indicates that palmitoylation serves as an additional level of regulatory control of FCRL4.

PURPOSE: Lymphomas often present a diagnostic challenge, and for some a delay in diagnosis can negatively influence outcomes of therapy. We established a nurse practitioner–led lymphoma rapid diagnosis clinic (LRDC) with the goal of reducing wait times to definitive diagnosis. We examined the initial 30-month experience of the LRDC, and results were compared with time periods before implementation of the clinic to determine program impact. METHODS: All patients referred to LRDC with suspicion of lymphoma from June 1, 2015 to Nov 30, 2017 were evaluated. Time from initial consultation to diagnosis was compared with patients diagnosed at our center with lymphoma in 2008 and 2012. Patient symptoms and relevant laboratory/imaging findings were collected to identify patterns of presentation and predictive factors for benign diagnoses. RESULTS: Of the 126 patients evaluated, 66 (52%) had confirmation of lymphoma diagnosis. Median time to lymphoma diagnosis was 16 days for patients assessed in LRDC and 28 days for historical controls ( P < .001). By univariable analysis, lymph node size greater than 3.4 cm and presence of mediastinal or abdominal adenopathy increased the likelihood of a diagnosis of malignancy, whereas younger age, being a nonsmoker, and prior rheumatologic condition were associated with a nonmalignant diagnosis. In multivariable analysis, lymph node size, age, and prior rheumatologic diagnosis remained significant. CONCLUSION: Establishing a nurse practitioner–led LRDC was effective in shortening time to diagnosis of lymphoma. Younger age, smaller lymph node size, and prior rheumatologic disorder reduced the likelihood of a cancer diagnosis in our patient population.