Challenges and solutions to superior chimeric antigen receptor-T design and deployment for B-cell lymphomas

Br J Haematol. 2023 Oct;203(2):161-168. doi: 10.1111/bjh.19001. Epub 2023 Jul 24.


Chimeric antigen receptor-T (CAR-T) therapies represent a major breakthrough in cancer medicine, given the ex vivo-based technology that harnesses the power of one's own immune system. These therapeutics have demonstrated remarkable success for relapsed/refractory B-cell lymphomas. Although more than a decade has passed since the initial introduction of CAR-T therapeutics for patients with leukaemia and lymphoma, there is still significant debate as to where CAR-T therapeutics fit into the management paradigm, as consensus guidelines are limited. Competing interventions deployed in subsequent lines of therapy for aggressive lymphoma include novel targeted agents, bispecific antibodies, and time-honoured stem cell transplant. In this focused review, we discuss the major obstacles to advancing the therapeutic reach for CAR-T products in early lines of therapy. Such barriers include antigen escape, "cold" tumour microenvironments, host inflammation and CAR-T cell exhaustion. We highlight solutions including point-of-care CAR-T manufacturing and early T lymphopheresis. We review the evidence basis for early CAR-T deployment for B-cell lymphomas in light of the recent Food and Drug Administration (FDA) approval of three first-in-class anti-CD3/CD20 bispecific antibodies-mosunetuzumab, epcoritamab and glofitamab. We propose practical recommendations for 2024.

Keywords: B cells; CAR-T therapies; bispecific antibodies; lymphoma; non-Hodgkin lymphoma.

Publication types

  • Review
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antibodies, Bispecific* / therapeutic use
  • Antineoplastic Agents*
  • Humans
  • Immunotherapy, Adoptive
  • Lymphoma* / therapy
  • Lymphoma, B-Cell* / pathology
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen*
  • Tumor Microenvironment


  • Receptors, Chimeric Antigen
  • glofitamab
  • Antibodies, Bispecific
  • Receptors, Antigen, T-Cell
  • Antineoplastic Agents