pTɑ Enhances CAR T-cell Function to Eradicate Liquid and Solid Tumors

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated durable responses in patients with hematological malignancies; however, this treatment lacks efficacy in solid tumors. Shi and colleagues found that the addition of the pre-TCR pTɑ invariant chain to the canonical 19-28z CAR enhances CAR T-cell function and expansion without promoting exhaustion. This novel pTɑ-containing CAR (19-28z-1A) demonstrated increased antitumor activity, as shown by sustained expansion and elevated cytokine production in response to antigen exposure compared to the 19-28z CAR in vitro. To test T-cell expansion in vivo, CAR T cells were infused into a B-ALL NALM6 mouse model. At six weeks post-infusion, almost all mice that received 19-28z CAR T cells had progressed, while 19-28z-1A CAR T cells led to tumor regression and, in most cases, tumor elimination. Gene set enrichment analysis from RNA sequencing conducted two weeks post-infusion highlighted ribosomal proteins and mRNA translation pathways as enriched with 19-28z-1A, suggesting that 1A CARs promote increased translation to maintain T-cell function. Phosphoproteomic analysis identified the mRNA translation master regulator Y-Box Binding Protein 1 (YBX1) as differentially phosphorylated in 19-28z-1A CAR T cells. YBX1 knockout reduced mRNA translation and T-cell expansion. Further, analysis of genes with increased translation efficiency in 19-28z-1A CAR T cells supported a role for YBX1 in mediating sustained translation through the TPT1 and eIF3 interactome. Conversely, 19-28z CAR T cells showed enrichment of genes associated with paused or stalled ribosomes. To assess the efficacy of 19-28z-1A CARs in solid tumors, CARs targeting CD70 (70-28z-1A) were constructed and tested in renal cell carcinoma and glioblastoma models. 70-28z-1A CAR T cells demonstrated increased expansion and persistence, with mice infused with 70-28z relapsing after 20 days, while 70-28z-1A CARs resulted in reduced tumor burden and survival up to 80 days. Preliminary safety testing revealed similar profiles between 28z and 28z-1A CARs in vivo. Overall, these data demonstrate improved functionality, potency, and persistence of 28z-1A CARs in both hematological and solid malignancies and propose novel strategies for optimal CAR T-cell development.Shi Y, Lopez MA, Kotchetkov IS, Jain N, Zhao Z, Halim L, et al. pTα enhances mRNA translation and potentiates CAR T cells for solid tumor eradication. Cell 2025 Dec 2 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.