Outcomes of Patients with Large B-cell Lymphoma Progressing after Axicabtagene Ciloleucel

Spiegel, Jay Y.; Dahiya, Saurabh; Jain, Michael D.; Tamaresis, John; Nastoupil, Loretta J.; Jacobs, Michael; Ghobadi, Armin; Lin, Yi; Lunning, Matthew A.; Lekakis, Lazaros J.; Reagan, Patrick M.; Oluwole, Olalekan O.; McGuirk, Joseph P.; Deol, Abhinav; Goy, André; Vu, Khoan; Andreadis, Charalambos; Muñoz, Javier; Bennani, N. Nora; Vose, Julie M.; Dorritie, Kathleen A.; Neelapu, Sattva S.; Locke, Frederick L.; Rapoport, Aaron P.; Hill, Brian T.; Miklos, David B.

doi:10.1182/blood.2020006245

Cited by 58 publications

(61 citation statements)

References 10 publications

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“…We also observed a significant incidence of CD19 + relapse, as reported in many previous trials of CAR19 for B-ALL and LBCL 61 , suggesting that potency toward the CD19 target may also be insufficient in some patients. Improvements in CAR manufacturing could prevent antigen + resistance, which likely results from T cell failure.…”

Section: Discussionsupporting

confidence: 84%

CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial

Spiegel

Patel

Muffly

et al. 2021

Nat Med

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301

214

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Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19− or CD19lo disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial (NCT03233854) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n = 17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n = 21), 62% of patients responded with 29% CR. Relapses were CD19−/lo in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22−/lo disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.

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Section: Discussionsupporting

confidence: 84%

CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial

Spiegel

Patel

Muffly

et al. 2021

Nat Med

Self Cite

301

214

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“…recently published the, until now, biggest trial reporting about salvage treatments after CAR T-cells. Interestingly, none of the reported patients was treated with Pola-BR ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

Salvage Therapy With Polatuzumab Vedotin, Bendamustine, and Rituximab Prior to Allogeneic Hematopoietic Transplantation in Patients With Aggressive Lymphomas Relapsing After Therapy With Chimeric Antigen Receptor T-Cells—Report on Two Cases

Gerhardt¹,

Jentzsch²,

Georgi

et al. 2021

Front. Oncol.

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Up to 60% of patients with aggressive B-cell lymphoma who receive chimeric antigen receptor (CAR) T-cell therapy experience treatment failure and subsequently have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a potentially curative approach for patients in this situation. Induction of a deep response prior to alloHSCT is crucial for long-term outcomes, but the optimal bridging strategy following relapse after CAR T-cell therapy has not yet been established. Polatuzumab vedotin, an antibody drug conjugate targeting CD79b, is a novel treatment option for use in combination with rituximab and bendamustine (Pola-BR) in relapsed or refractory disease. Patients: We report two heavily pretreated patients with primary refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL) respectively who relapsed after therapy with CAR T-cells with both nodal and extranodal manifestations of the disease. After application of three courses of Pola-BR both patients achieved a complete metabolic remission. Both patients underwent alloHSCT from a human leukocyte antigen (HLA)-mismatched donor following conditioning with busulfan and fludarabine and are disease free 362 days and 195 days after alloHSCT respectively. We conclude that Pola-BR can be an effective bridging therapy before alloHSCT of patients relapsing after CAR T-cell therapy. Further studies will be necessary to define the depth and durability of remission of this salvage regimen before alloHSCT.

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“…A recent CIBMTR analysis demonstrated a remarkable decline in the use of alloSCT for DLBCL and a sharp increase in the use of CAR T-cell therapy. Although CAR T-cell therapy offers durable remissions in relapsed DLBCL patients, approximately 50% of these patients still experience disease relapse, and their outcomes are dismal [ 43 , 44 ]. AlloSCT has a role in such circumstances [ 45 , 46 ].…”

Section: Allogeneic Stem Cell Transplantmentioning

confidence: 99%

“…Among 74% who received further therapy, the ORR was 29%, with a CR of 17%, and a median PFS of 55 days. CD19 losses were found in approximately 30% of patients at progression [ 44 ]. Antigen escape is one of the mechanisms of CAR T-cell resistance, where the malignant cells that are treated with CAR T-cells display the partial or complete loss of the CD19 antigen.…”

Section: Chimeric Antigen Receptor T-cell Therapymentioning

confidence: 99%

Immunotherapy for Diffuse Large B-Cell Lymphoma: Current Landscape and Future Directions

Modi

Potugari

Uberti

2021

Cancers

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Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. B-cell receptor (BCR) pathway is essential for malignant B-cell growth, survival, and proliferation. Various immune cells, including T-cells and macrophages in the tumor microenvironment (TME) contribute to tumor cell survival and pathogenesis of chemo-resistance. The presence of many targets on the malignant B-cells and in the TME has led to emergence of novel therapeutic agents. Stem cell transplant is the oldest treatment modality leveraging immune system in DLBCL. Subsequently, CD20 targeting monoclonal antibody and chimeric antigen receptor (CAR) T-cell therapy changed the treatment landscape of DLBCL. Recently, multiple novel immunotherapeutic agents have been added in the armamentarium for the management of DLBCL, and many are under development. In this review article, we will review latest updates of immunotherapeutic agents in the management of DLBCL.

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Outcomes of Patients with Large B-cell Lymphoma Progressing after Axicabtagene Ciloleucel

Cited by 58 publications

References 10 publications

CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial

CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial

Salvage Therapy With Polatuzumab Vedotin, Bendamustine, and Rituximab Prior to Allogeneic Hematopoietic Transplantation in Patients With Aggressive Lymphomas Relapsing After Therapy With Chimeric Antigen Receptor T-Cells—Report on Two Cases

Immunotherapy for Diffuse Large B-Cell Lymphoma: Current Landscape and Future Directions

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