Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial

Shah, Nirav N.; Johnson, Bryon D.; Schneider, Dina; Zhu, Fenlu; Szabó, Anikó; Keever-Taylor, Carolyn A.; Krueger, Winfried; Worden, Andrew; Kadan, Michael J.; Yim, Sharon; Cunningham, Ashley M.; Hamadani, Mehdi; Fenske, Timothy S.; Dropulić, Boro; Orentas, Rimas J.; Hari, Parameswaran

doi:10.1038/s41591-020-1081-3

Cited by 314 publications

(253 citation statements)

References 30 publications

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“…Targeted antigen-negative relapse is one of the main reasons for resistance to CD19-directed CAR T-cell therapy and accounts for~9-25% of cases of relapse in other hematological cancers 3,4,6,7 . In addition to antigen loss, immune-mediated rejection of the murine construct may play a role in resistance 15 . We did observe low level anti-drug antibodies (ADAs) at 6 months post first infusion, which persisted during the retreatment.…”

Section: Discussionmentioning

confidence: 99%

Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma

Samur¹,

Fulciniti²,

Samur³

et al. 2021

Nat Commun

233

143

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BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.

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Section: Discussionmentioning

confidence: 99%

Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma

Samur¹,

Fulciniti²,

Samur³

et al. 2021

Nat Commun

233

143

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“…These ndings support the idea that additional therapies enhancing antitumor e cacy, such as our approach to combine erlotinib with CAR T cells, may be valuable to prevent antigen escape. Recent phase I clinical trial revealed that bispeci c anti-CD20, anti-CD19 CAR T cells may improve clinical responses by mitigating target antigen downregulation for relapsed B cell malignancies 36 . In this study, combining CAR T cells and erlotinib therapy showed the capability to lysing AXL-positive HCC827-ER3 cells, meanwhile, erlotinib itself can target and suppress AXL-low or -negative tumor cells, which is a unique advantage of this combination strategy to overcome tumor heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

Use of AXL-specific CAR T cells to treat non-small-cell lung cancer

Zhang

Cao

Liu

et al. 2021

Preprint

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The application of Chimeric antigen receptor (CAR) T cells in solid tumors is hindered by lack of tumor specific targets and inefficient T cell infiltration in tumor. It has been postulated that AXL may be an ideal immunotherapy target for non-small-cell lung cancer (NSCLC). Here, we screened 208 non-tumor samples from 22 types of human organs or tissues and 90 tumor samples from NSCLC patients by immunohistochemistry or Western Blotting and identified that AXL was rarely expressed in normal tissues but highly expressed in 69% NSCLC samples, suggesting AXL is an ideal target for CAR T cell therapy for lung cancer. We generated low-, mediate-, high-affinity AXL-CARs and evaluated their killing effect on NSCLC. Our data demonstrated antitumor effects of AXL-CAR T cell therapy for various NSCLC models both in vitro and in vivo. AXL-CAR T cells alone exerted strong antitumor effect in subcutaneous lung cancer cell derived xenograft (CDX), pulmonary metastases CDX, and intraperitoneal CDX models. Intraperitoneal delivery of CAR T cells resulted in superior tumor killing effects compared with systemic infusions for the intraperitoneal CDX tumor models. AXL-CAR T combined with microwave ablation (MWA) or EGFR-TKI resulted in enhanced killing effect and CAR-T cell infiltration in vivo. Together, our current study suggests that systemic or regional infusion of AXL-CAR T cell alone or combination with other therapies might have potential translatable value for the treatment of NSCLC in clinical situation.

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“…For instance, in multiple myeloma (MM), there are a host of emerging BiTEs as well as CAR T cells targeting several different MM antigens, including B-cell maturation antigen, CD38, and CD138, among others. [46][47][48] CD20 represents another attractive target for B-cell lymphomas, and certainly both CD20 targeted BiTEs and combinatorial CD19-CD20 CAR T-cell constructs 49 are actively being tested. Further experiences with these novel approaches will provide greater insight into the merits and limitations of CAR T cells vs BiTEs beyond B-ALL, but the framework set forth will likely apply.…”

Section: Sequential Therapy: Considerationsmentioning

confidence: 99%

“…Advances in combinatorial antigen CAR T-cell strategies may further optimize the potential for durable remissions above and beyond BiTEs as these novel constructs evolve. 34…”

mentioning

confidence: 99%

CAR T cells better than BiTEs

Molina

Shah

2021

Blood Advances

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This article has a companion Counterpoint by Subklewe. Despite significant advances in treatment regimens and outcomes in B-cell acute lymphoblastic leukemia (B-ALL), long-term survival remains poor for the 15% to 20% of pediatric patients and 50% of adults with relapsed or refractory (r/r) disease. 1-3 The emergence of immunotherapeutic strategies that use B-cell antigen-targeted single-chain variable fragments to direct T cells to specific surface antigens on BALL cells has revolutionized outcomes. These strategies include the US Food and Drug Administration (FDA)-approved bispecific T-cell engager (BiTE) blinatumomab and chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel. 4 Even though both therapies target CD19, outcomes vary significantly. We discuss considerations and potential benefits of the preferential use of CAR T-cell therapy over BiTE in r/r BALL , which can serve as a framework for evaluation of approaches with alternative antigen-targeting strategies. Efficacy of CAR vs BiTE: response rates, trafficking, and durability In the phase 2/3 trials leading to the FDA approval of blinatumomab in 2014, the objective response rate to blinatumomab in adult patients was 36% to 44%. Of those achieving a complete remission (CR), 63% to 88% had a minimal residual disease (MRD)-negative remission. 5-9 Importantly, of 70 pediatric patients evaluated, 39% achieved CR with only 14 (20%) being MRD negative. 10 Despite an improvement over responses with conventional salvage chemotherapy, as well as improved response rates for those with MRD-level disease, 11 results of the blinatumomab phase 2/3 and retrospective adult trials indicate that a significant portion of patients are resistant to blinatumomab (Table 1). 12

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Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial

Cited by 314 publications

References 30 publications

Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma

Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma

Use of AXL-specific CAR T cells to treat non-small-cell lung cancer

CAR T cells better than BiTEs

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