CD19 chimeric antigen receptor (CAR) T-cell therapy has become the standard of care in relapse and/or refractory B-cell malignancies. Up to 30% to 60% of patients experience relapsed disease because of the emergence of CD19low or CD19- tumor cell clones. Although bispecific CD19/CD22 CAR T cells have been explored, limited persistence and antigen downregulation of CD19 and/or CD22 have compromised their efficacy in relapsing patients. A comprehensive analysis of CD22 expression revealed that CD22 is ubiquitously expressed across all subgroups of B-cell lymphomas and B-cell leukemias, establishing CD22 as a valuable immunotherapeutic target. Using a humanized mouse model with a diverse human T-cell receptor (TCR) repertoire, we identified a high-affinity TCR targeting a CD22 epitope presented by HLA-A∗02:01. In vitro, this TCR demonstrated high specificity and efficacy in both CD22+ cell lines and primary patient-derived tumor samples. Importantly, CD22 TCR T cells outperformed CD22 CAR T cells in recognizing cells with low CD22 surface expression, including CD22low Nalm6 cells that emerged after in vivo CD19 T-cell treatment. Unlike CD22 CAR T cells, CD22 TCR T cells effectively recognized tumor cells that predominantly express intracellular CD22. Notably, in vivo validation in a Nalm6 B-cell leukemia model confirmed the superior activity of CD22 TCR T cells against CD22low cells compared to CD22 CAR T cells. In conclusion, our findings provide strong preclinical evidence supporting CD22 TCR-based therapy as a potent treatment option for CD22low B-cell malignancies, including patients who relapsed after CD19 CAR T-cell therapy.

In multiple myeloma (MM), cell-specific antigens are valuable targets for developing effective T-cell-engaging therapeutics that can provide good immune responses. Achieving a sustained immune response in recurrent MM, however, remains challenging. Ramantamig (JNJ-79635322) is a trispecific antibody targeting BCMA (B-cell maturation antigen) and GPRC5D (G-protein-coupled receptor family C group 5 member D), both of which are highly expressed on plasmablasts and plasma cells in samples from patients with myeloma. Dual antigen recognition on malignant plasma cells by a trispecific T-cell-engaging antibody could potentially enhance tumor binding through increased avidity, resulting in efficient depletion of the malignant clonal populations, targeting of tumor heterogeneity, and prevention of tumor antigen loss-mediated resistance. At subnanomolar ranges, ramantamig induced potent cytotoxicity in cancer cell lines with concomitant T-cell activation. Ramantamig efficiently depleted both dual- and single-target-expressing MM cell lines. In addition, it induced dose-dependent depletion of malignant plasma cells in samples from patients with MM both in an ex vivo T-cell coculture assay and in healthy fresh whole blood cocultured with H929 MM cells to mimic physiological conditions. Ramantamig exhibited potent antitumor activity in a murine xenograft prevention model (single-target-expressing clonal cells) and 2 tumor regression models. The potent and selective antitumor activity of ramantamig, with a clonal-depleting ability in vitro, ex vivo, and in vivo, warrants clinical evaluation of its ability to induce durable responses in myeloma. Phase 1 clinical trials are ongoing for patients with relapsed/refractory MM. These trials are registered at www.clinicaltrials.gov as NCT05652335 and NCT06768489.

Clinical trial eligibility criteria select a target population and reduce anticipated risks for participants but may unnecessarily limit participation both overall and differently across demographic groups. We previously abstracted eligibility criteria for 190 phase 2/3 acute myeloid leukemia (AML) trials and used US Food and Drug Administration and professional society guidance on modernizing criteria to develop alternative, safety-based eligibility criteria for each trial. In this analysis, these trial- and safety-based eligibility criteria sets were applied to a retrospective cohort of 2226 newly diagnosed patients across 8 hospitals to assess the impact on eligibility. Eligibility proportions increased from a median of 47.9% with trial-based criteria to 84.2% with safety-based criteria (median difference, 30.0%; P< .001); excluding age criteria, the increase was 11.5% (P< .001). Non-Hispanic (NH) Asian, NH Black, NH White, and Hispanic patients were eligible for median proportions of 41.1%, 44.0%, 47.9%, and 50.0%, respectively, with trial-based criteria, increasing by 27.9% to 31.6% when using safety-based criteria (within-group changes, all P< .001; between-group changes, all P> .05). Excluding age criteria, increases were between 10.0% and 11.9%. Moving from trial- to safety-based criteria decreased the proportion of trials with significant eligibility differences between NH White and NH Asian (-11.1%), NH Black (-4.2%), and Hispanic (-12.1%) patients. Criteria significantly associated with increased eligibility and decreased between-group differences in eligibility were coronary artery disease, congestive heart failure, aspartate transaminase level, upper age limits, and previous malignancy. These data suggest that modernization of eligibility for AML trials to focus on safety-based criteria can improve both overall enrollment and population representation.

The transcription factor MECOM, located at 3q26, is essential for hematopoietic stem cells in healthy individuals. Enhancer translocations, due to 3q26 rearrangements, drive out-of-context MECOM expression in one of the most aggressive subtypes of acute myeloid leukemia (AML). Aberrantly expressed MECOM is essential for the survival and immature phenotype of these leukemia cells. Direct depletion of MECOM using an endogenous auxin-inducible degron immediately upregulates expression of CEBPA, which encodes a transcription factor required for neutrophil development and is frequently mutated in other AML subtypes. MECOM depletion is accompanied by a severe loss of CD34 and gain of mature myeloid cell surface marker CD15. MECOM exerts its inhibitory effect on differentiation by binding to the +42-kilobase CEBPA enhancer. This is partially dependent on the interaction between MECOM and its corepressor CTBP2. We demonstrate that CEBPA overexpression can bypass the MECOM-mediated block of differentiation. In addition, patients with AML with MECOM overexpression through enhancer hijacking show significantly reduced CEBPA levels. Our study directly connects 2 major players in normal and malignant hematopoiesis, MECOM and CEBPA, and unveils how MECOM maintains self-renewal by repressing CEBPA-induced differentiation.