In the wake of the 10-year anniversary since the introduction of chimeric antigen receptor-T (CAR-T) cell therapies to the market, the field of B cell lymphoma has seen remarkable advances since these therapies first arrived at the bedside in 2017. Modern data from longitudinal readouts attests to the high depth and durability of response to CAR-T therapies in many patients with B cell lymphomas; however, approximately 50% of patients continue to have relapsed/refractory disease even after receipt of conventional CAR-T constructs. In this review, we discuss the mechanisms underlying primary and secondary refractoriness to conventional single-targeting CAR-T therapies for B cell lymphomas and explore the ongoing challenges with existing CAR constructs. We discuss the prospects for adaptable multi-antigen targeting via the use of bivalent CAR and bicistronic CAR functionalities as informed by recent advances in synthetic immunobiology. We explore contemporary efforts, mostly Phase 1 and 2 trials, involving bivalent CAR and bicistronic CAR constructs at the cutting edge of clinical translation. Finally, we propose evidence-based solutions to help improve the translational success of multi-antigen CAR-T therapy, including optimizing construct architecture, expanding the targetable antigen landscape, and improving scalability. These solutions for multi-antigen targeting in next-generation CARs may have substantial benefits in the coming years.
Toshali Pandey, D. Samat, Saurabh Dahiya et al.· Frontiers in Immunology· 1 citation
Advances in the molecular characterization of acute myeloid leukemia (AML) in recent decades have driven the development and clinical introduction of several targeted therapies, and menin inhibitors are the most recent additions to the therapeutic arsenal of AML treatments. The KMT2A and NPM1 loci have been the focus of intense investigation over the past two decades because of their well-established roles leukemogenesis, particularly in pre-clinical models of AML involving human xenografts. The ability of KMT2A and NPM1 aberrancies to drive and sustain leukemogenesis has provided a strong rationale for the development of therapeutic strategies to disrupt these molecular pathways. Menin inhibitors preferentially eliminate clones harboring KMT2A rearrangements or NPM1 mutations due to the dependence of these leukemia cells on the menin–KMT2A complex and its downstream HOXA9/MEIS signaling to sustain leukemic self-renewal and disease maintenance. In this review, we discuss the biological rationale for menin–MLL disruption in patients with acute leukemia with KMT2A rearrangement or NPM1 mutation. We explore data from the landmark AUGMENT-101 and KOMET-001 trials, which have led to regulatory approval of revumenib and ziftomenib for select patients. We also explore cutting-edge studies using menin inhibitors in combination strategies, including data from KOMET-007. The evidence supporting combination approaches remains based on early-phase, single-arm trials with relatively short follow-up, and longer-term and comparative data are needed to define their clinical benefit. We highlight resistance mechanisms that have emerged from the use of contemporary menin inhibitors and efforts aimed at addressing this resistance, with a focus on emerging clinical data on enzomenib and bleximenib. Finally, we discuss prospects on the putative role of menin inhibitors in the measurable residual disease (MRD)-positive and maintenance settings in AML. Menin inhibitors have successfully transitioned from biological proof-of-concept to approved targeted therapy, and future advances will depend on rational front line combination strategies, MRD-guided treatment, post-transplant maintenance strategies, and therapeutic sequencing informed by mechanisms of resistance.
Tina Y. Zhang, Shyam A. Patel, T. Badar· Cancers· 0 citations
