Sequential loss of tumor surface antigens following chimeric antigen receptor T-cell therapies in diffuse large B-cell lymphoma

Abstract

. Sequential loss of tumor surface antigens following chimeric antigen receptor T-cell therapies in diffuse large B-cell lymphoma.

Bispecific Antibodies in the Treatment of Hematologic Malignancies

“…The approach has also shown potential in patients with B‐cell lymphomas and, shortly following the approval of tisagenlecleucel, the anti‐CD19 T‐cell therapy axicabtagene ciloleucel (Yescarta; Kite Pharma, Santa Monica, CA) was approved for the treatment of adult patients with r/r large B‐cell lymphoma . However, resistance can be a problem, and the loss of the target antigen on tumor cells has been cited as mechanism of resistance to anti‐CD19 CAR T cells . CAR T‐cell therapy is also associated with CRS and neurotoxicity .…”

“…33 However, resistance can be a problem, and the loss of the target antigen on tumor cells has been cited as mechanism of resistance to anti-CD19 CAR T cells. 34 CAR T-cell therapy is also associated with CRS and neurotoxicity. 35,36 In light of this, in 2018, tocilizumab (a recombinant humanized mAb directed against the IL-6 receptor) was approved by the FDA for the treatment of severe or life-threatening CRS following CAR T-cell therapy.…”

Immunobiology of chimeric antigen receptor T cells and novel designs

“…Such mechanisms, suggest that absence of CD19 antigen (or its cognate epitope) may not only occur in response to immunological pressure, but may exist in a subpopulation prior to selective immune pressure . While the majority of CD19 antigen loss has been described in ALL, similar findings are beginning to emerge after the treatment of Diffuse Large B cell Lymphomas (DLBCL) following CD19 directed CAR T cells . Furthermore, findings of antigen loss after CAR T cell therapy extend beyond cancers of the B cell lineage, as loss of the antigens IL3Rα2 and EGFRvIII have been observed in preclinical models and in patients after CAR T cell treatment of glioblastoma, suggesting that antigen loss will be a recurring obstacle across a range of CAR T cell therapies …”

“…106,109 While the majority of CD19 antigen loss has been described in ALL, similar findings are beginning to emerge after the treatment of Diffuse Large B cell Lymphomas (DLBCL) following CD19 directed CAR T cells. 110 Furthermore, findings of antigen loss after CAR T cell therapy extend beyond cancers of the B cell lineage, as loss of the antigens IL3Rα2 and EGFRvIII have been observed in preclinical models and in patients after CAR T cell treatment of glioblastoma, suggesting that antigen loss will be a recurring obstacle across a range of CAR T cell therapies. 111,112 Because the use of CAR T cells targeting a single antigen may allow for the outgrowth of antigen negative cells, resistance may be overcome by the simultaneous targeting of multiple antigens.…”

Diagnosis of Lymphoid Lesions in Limited Samples

“…• Loss of target antigens from the cell surface (eg, loss of CD20 in patients treated with rituximab, CD30 following treatment with brentuximab, or multiple target antigens following treatment with chimeric antigen receptor T cells) 50-52 • Insufficient/limited diagnostic material in samples obtained from lymph nodes or other sites that are necrotic or fibrotic following chemotherapy or radiation therapy 53 • The need to determine if residual lymphoma or minimal residual disease is present following treatment 52,53 Interpretation of biopsy specimens after therapy can be difficult and requires considering potential confounders like tumor viability, radiation atypia, sample adequacy, and the possibility of histologic transformation. 54 Correlation with serial CT and PET/CTs, clinical symptoms, and laboratory parameters of disease activity (LDH, β2-microglobulin) for evaluation of response to therapy, disease progression, potential transformation, and the prospect of participating in specific clinical trials will determine the need to undergo repeat or additional sampling.…”