Chimeric antigen receptor T-cell (CART) immunotherapy led to unprecedented responses in patients with refractory/relapsed B-cell non-Hodgkin lymphoma (NHL); nevertheless, two thirds of patients experience treatment failure. Resistance to apoptosis is a key feature of cancer cells, and it is associated with treatment failure. In 87 patients with NHL treated with anti-CD19 CART, we found that chromosomal alteration of B-cell lymphoma 2 (BCL-2), a critical antiapoptotic regulator, in lymphoma cells was associated with reduced survival. Therefore, we combined CART19 with the FDA-approved BCL-2 inhibitor venetoclax and demonstrated in vivo synergy in venetoclax-sensitive NHL. However, higher venetoclax doses needed for venetoclax-resistant lymphomas resulted in CART toxicity. To overcome this limitation, we developed venetoclax-resistant CART by overexpressing mutated BCL-2(F104L), which is not recognized by venetoclax. Notably, BCL-2(F104L)-CART19 synergized with venetoclax in multiple lymphoma xenograft models. Furthermore, we uncovered that BCL-2 overexpression in T cells intrinsically enhanced CART antitumor activity in preclinical models and in patients by prolonging CART persistence. Significance: This study highlights the role of BCL-2 in resistance to CART immunotherapy for cancer and introduces a novel concept for combination therapies—the engineering of CART cells to make them resistant to proapoptotic small molecules, thereby enhancing the therapeutic index of these combination therapies. This article is highlighted in the In This Issue feature, p. 2221

Most patients treated with US Food and Drug Administration (FDA)–approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.

Current US Food and Drug Administration–approved chimeric antigen receptor (CAR) T cell therapies for B cell leukemias and lymphomas target CD19, which is widely expressed across the B cell lineage, often leading to on-target, off-tumor B cell depletion, prolonged immune suppression, and antigen-negative escape in a subset of patients. In contrast, B cell receptor (BcR) signaling is essential for the survival of most mature B cell neoplasms, and BcRs carrying the immunoglobulin heavy variable gene IGHV4-34 are highly enriched in B cell malignancies compared with normal B cells. Further, self-reactive IGHV4-34 ⁺ serum autoantibodies are enriched in aggressive systemic lupus erythematosus (SLE) and other autoimmune diseases. Here, we developed CAR T cells targeting the BcR carrying IGHV4-34 (CART4-34). We found that CART4-34 showed specific cytotoxicity and cytokine secretion toward IGHV4-34 ⁺ malignant B cells. In addition, although CD19 was down-regulated upon relapse after treatment with CART19, IGHV4-34 ⁺ BcR levels remained intact upon relapse after treatment with CART4-34, suggesting reduced risk of antigen-negative escape. In IGHV4-34 ⁺ HBL1 cell line–derived xenograft mouse models, CART4-34 showed robust expansion and antitumor activity comparable to those of CART19. Optimized CAR:BcR binding using shorter CAR hinge domains improved immune synapse morphology and in vivo activity. In addition, we showed that CART4-34 could target human IGHV4-34 ⁺ SLE B cells and deplete IGHV4-34 ⁺ autoantibodies ex vivo, without targeting healthy B cells or affecting total IgG titers. In conclusion, we developed a CAR T cell product that specifically targets pathogenic B cells in lymphoid malignancies and SLE, offering potential for precision cell therapy for these indications.

Accurate estimation of the progression risk after first-line therapy represents an unmet clinical need in diffuse large B-cell lymphoma (DLBCL). Baseline (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) parameters, together with genetic analysis of lymphoma cells, could refine the prediction of treatment failure. We evaluated the combined impact of mutation profiling and baseline PET/CT functional parameters on the outcome of DLBCL patients treated with the R-CHOP14 regimen in the SAKK38/07 clinical trial (NCT00544219). The concomitant presence of mutated SOCS1 with wild-type CREBBP and EP300 defined a group of patients with a favorable prognosis and 2-year progression-free survival (PFS) of 100%. Using an unsupervised recursive partitioning approach, we generated a classification-tree algorithm that predicts treatment outcomes. Patients with elevated metabolic tumor volume (MTV) and high metabolic heterogeneity (MH) (15%) had the highest risk of relapse. Patients with low MTV and favorable mutational profile (9%) had the lowest risk, while the remaining patients constituted the intermediate-risk group (76%). The resulting model stratified patients among three groups with 2-year PFS of 100%, 82%, and 42%, respectively (p < 0.001).

Chimeric antigen receptor T cell (CAR-T) therapies are now standard-of-care for several B-cell malignancies, and additional indications are being evaluated. In this review, we survey data on how outcomes after CAR-T therapies vary according to age, race, and ethnicity. We also review the representation of age, racial, and ethnic groups in key CAR-T clinical trials. We focus on B-cell acute lymphoblastic leukemia, B-cell non-Hodgkin’s lymphoma, and multiple myeloma.