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CD58 aberrations limit durable responses to CD19 CAR T-cell therapy

Presented by
Dr Robbie Majzner, Stanford University, California, USA
ASH 2020
CD58 mutations have been reported in many cancers and are likely to play a role in immune evasion for chimaeric antigen receptor (CAR) T cells. CD58 status is found to be an important biomarker for durable response to CAR T cells in large B-cell lymphomas (LBCL). Dr Robbie Majzner (Stanford University, California, USA) modelled the biologic basis for this finding and generated CAR T cells capable of overcoming CD58 loss in B-cell malignancies [1].

CD19 CAR T cells have revolutionised the treatment of relapsed/refractory (R/R) LBCL, resulting in durable and complete responses in approximately 40-50% of patients [2]. “We wanted to focus on patients who do not obtain durable and complete responses, because the outcome of these patients is really poor, with a median overall survival (OS) of <200 days [3],” Dr Majzner explained [1]. “Because CAR T cells are able to induce long-term remission in patients, we feel that if we can get the initial response rate up and find the mechanisms of resistance and engineer around that, we can cure more patients.” Besides a loss or decrease in CD19 expression, no studies have identified tumour-specific factors driving resistance to CAR T cells in LBCL. Mutations in and loss of expression of CD58 have been described in approximately 20% of LBCL cases. CD58 loss or mutation has been linked to immune resistance in LBCL [1].

Dr Majzner and his team evaluated CD58 status in 51 R/R LBCL patients with axicabtagene ciloleucel (axi-cel) through immunohistochemistry on tumour biopsy samples and/or deep sequencing of circulating tumour DNA; 24% of these patients had a CD58 aberration. Progression-free survival (PFS) was significantly decreased in patients with a CD58 aberration (median 3 months vs not reached for CD58 intact; P<0.0001). Only 1 patient with a CD58 alteration achieved a durable, complete response to axi-cel and the remaining 11 patients progressed, most commonly after a period of initial response [1].

To overcome CD58 loss in LBCL, the researchers generated second- and third-generation CAR T-cell constructs. While these constructs demonstrated increased potency against CD58 knock-out cells in vitro, they were unable to ultimately overcome CD58 loss in vivo. However, when CARs were co-expressed with an additional CD2 receptor, they mediated significant anti-tumour activity in vivo, overcoming CD58 knockout in tumour cells [1].

These data provide rationale for investigating CD58 status for patients receiving CAR-based therapeutics. “We have now been able to engineer CARs to integrate CD58-CD2 signalling in a specific manner to overcome CD58 loss and re-establish CAR efficacy, independent of CD58 on the tumour cell line,” Dr Majzner concluded. “We think that this will end up in other malignancies as well, because CD58 mutations are common in other cancers, including myeloma and Hodgkin lymphoma, and are likely able to mediate resistance to other CARs and immunotherapeutics.”

    1. Majzner RG, et al. CD58 Aberrations Limit Durable Responses to CD19 CAR in Large B Cell Lymphoma Patients Treated with Axicabtagene Ciloleucel but Can be Overcome through Novel CAR Engineering. 62nd ASH Annual Meeting, 5-8 December 2020. Abstract 556.
    2. Neelapu SS, et al. N Engl J Med. 2017;377:2531-44.
    3. Spiegel JY, et al. Blood. 2020;blood.2020006245.

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