In a phase 1 clinical study of 32 participants with advanced B cell non-Hodgkin lymphoma, immunotherapy with defined subsets of T cells, rather than whole T cell populations, showed strong antitumor activity. The findings suggest that pinning down a few key variables - the optimal T cell combinations, dosage, and pretreatment chemotherapy regimen - is critical to unlocking the full potential of chimeric antigen receptor (CAR)-modified T cell therapies, an approach that reprograms T cells with artificial receptors designed to target tumor cells. While the therapy is moving toward the clinic at a rapid pace, inconsistencies in CAR-T cell compositions pose a major hurdle. In an effort to streamline CAR-T cell therapy for better patient outcomes, Cameron Turtle and colleagues treated subjects with specific ratios of CD4 and CD8 CAR-T cells at fixed concentrations with or without fludarabine, a type of chemotherapy often administered prior to CAR-T therapy, to enhance its potency. Patients in the fludarabine cohort demonstrated greater CAR-T cell expansion and persistence against the cancer, in addition to higher response rates, with 50% achieving complete remission compared to 8% of patients who did not receive fludarabine. Although fludarabine treatment was generally associated with greater toxicity, the researchers successfully detected biomarkers in the blood indicative of toxicity after CAR-T cell infusion, offering a potential strategy for identifying high-risk patients who may benefit from early intervention. These collective results offer new insights into strategies for boosting the overall efficacy and safety of CAR-T cell therapies.