Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence

Katsarou, Afroditi; Sjöstrand, Maria; Naik, Jyoti; Mansilla-Soto, Jorge; Kefala, Dionysia; Kladis, Georgios; Nianias, Alexandros; Ruiter, Ruud; Poels, Renée; Sarkar, Irene; Patankar, Yash R.; Merino, Elena; Reijmers, Rogier M.; Frerichs, Kristine A.; Yuan, Huipin; Bruijn, Joost D. de; Stroopinsky, Dina; Avigan, David; Donk, Niels W.C.J. van de; Zweegman, Sonja; Mutis, Tuna; Sadelain, Michel; Groen, Richard W.J.; Themeli, Maria

doi:10.1126/scitranslmed.abh1962

Cited by 52 publications

(23 citation statements)

References 51 publications

(83 reference statements)

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“…This suggests that the CCR may contribute to target cell docking under some circumstances, as described for other pCARs ( 10 ). In keeping with this, recently published data indicate that co-expression of a CCR together with a CAR leads to increased functional avidity and enhanced sensitivity to detect tumor cells that express low levels of CAR target antigen ( 40 ). When administered at a low dose to mice with an established Nalm-6 leukemic burden, all pCAR T-cells significantly outperformed their CAR counterparts, or the parental F-2 CAR, in which an unmodified FMC63 scFv conferred CD19 specificity.…”

Section: Discussionmentioning

confidence: 74%

Engineering of an Avidity-Optimized CD19-Specific Parallel Chimeric Antigen Receptor That Delivers Dual CD28 and 4-1BB Co-Stimulation

Halim

Das²,

Larcombe-Young

et al. 2022

Front. Immunol.

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Co-stimulation is critical to the function of chimeric antigen receptor (CAR) T-cells. Previously, we demonstrated that dual co-stimulation can be effectively harnessed by a parallel (p)CAR architecture in which a CD28-containing second generation CAR is co-expressed with a 4-1BB containing chimeric co-stimulatory receptor (CCR). When compared to linear CARs, pCAR-engineered T-cells elicit superior anti-tumor activity in a range of pre-clinical models. Since CD19 is the best validated clinical target for cellular immunotherapy, we evaluated a panel of CD19-specific CAR and pCAR T-cells in this study. First, we generated a panel of single chain antibody fragments (scFvs) by alanine scanning mutagenesis of the CD19-specific FMC63 scFv (VH domain) and these were incorporated into second generation CD28+CD3ζ CARs. The resulting panel of CAR T-cells demonstrated a broad range of CD19 binding ability and avidity for CD19-expressing tumor cells. Each scFv-modified CAR was then converted into a pCAR by co-expression of an FMC63 scFv-targeted CCR with a 4-1BB endodomain. When compared to second generation CARs that contained an unmodified or mutated FMC63 scFv, each pCAR demonstrated a significant enhancement of tumor re-stimulation potential and IL-2 release, reduced exhaustion marker expression and enhanced therapeutic efficacy in mice with established Nalm-6 leukemic xenografts. These data reinforce the evidence that the pCAR platform delivers enhanced anti-tumor activity through effective provision of dual co-stimulation. Greatest anti-tumor activity was noted for intermediate avidity CAR T-cells and derived pCARs, raising the possibility that effector to target cell avidity is an important determinant of efficacy.

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Section: Discussionmentioning

confidence: 74%

Engineering of an Avidity-Optimized CD19-Specific Parallel Chimeric Antigen Receptor That Delivers Dual CD28 and 4-1BB Co-Stimulation

Halim

Das²,

Larcombe-Young

et al. 2022

Front. Immunol.

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“…CAR-T cell therapy can provide a high CR/MRD negative response rate without maintenance, but response durations can be variable. Accordingly, much effort is currently being directed to increasing persistence of CAR-T cells in myeloma [ 76 , 77 ]. Achievement of that goal will permit studies to address questions related to response-adapted treatments in the future.…”

Section: Response Adapted Therapeutic Strategies Including Discontinu...mentioning

confidence: 99%

Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: Consensus recommendations of the NCI Multiple Myeloma Steering Committee

et al. 2022

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A wide variety of new therapeutic options for Multiple Myeloma (MM) have recently become available, extending progression-free and overall survival for patients in meaningful ways. However, these treatments are not curative, and patients eventually relapse, necessitating decisions on the appropriate choice of treatment(s) for the next phase of the disease. Additionally, an important subset of MM patients will prove to be refractory to the majority of the available treatments, requiring selection of effective therapies from the remaining options. Immunomodulatory agents (IMiDs), proteasome inhibitors, monoclonal antibodies, and alkylating agents are the major classes of MM therapies, with several options in each class. Patients who are refractory to one agent in a class may be responsive to a related compound or to a drug from a different class. However, rules for selection of alternative treatments in these situations are somewhat empirical and later phase clinical trials to inform those choices are ongoing. To address these issues the NCI Multiple Myeloma Steering Committee formed a relapsed/refractory working group to review optimal treatment choices, timing, and sequencing and provide recommendations. Additional issues considered include the role of salvage autologous stem cell transplantation, risk stratification, targeted approaches for genetic subsets of MM, appropriate clinical trial endpoints, and promising investigational agents. This report summarizes the deliberations of the working group and suggests potential avenues of research to improve the precision, timing, and durability of treatments for Myeloma.

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“…46 Alternatively, including a chimeric co-stimulatory receptor, which binds to a second tumor antigen and provides an additional co-stimulatory signal, improves BCMA-and CD19-targeting CAR T cells against tumor cells with low antigen density in preclinical models. 47 Decreased activation of CAR T cells resulting from antigen loss by the tumor cell is one mechanism by which tumor cells evade CAR T cell killing by single-antigen-targeting CAR T cells. This can be caused by CAR T cell-induced immune pressure, where cancer cells modulate their respective target antigens, either by disappearance of detectable antigen (loss) or lowered expression of the antigen to a level below a threshold required for CAR T cell activity (escape).…”

Section: Llmentioning

confidence: 99%

Understanding CAR T cell-tumor interactions: Paving the way for successful clinical outcomes

Korell

Berger

Maus

2022

Med

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Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence

Abstract: Combination of a CAR and a chimeric costimulatory receptor augments cytotoxicity and durability of T cells and elimination of antigen-low tumors.

Cited by 52 publications

References 51 publications

Engineering of an Avidity-Optimized CD19-Specific Parallel Chimeric Antigen Receptor That Delivers Dual CD28 and 4-1BB Co-Stimulation

Engineering of an Avidity-Optimized CD19-Specific Parallel Chimeric Antigen Receptor That Delivers Dual CD28 and 4-1BB Co-Stimulation

Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: Consensus recommendations of the NCI Multiple Myeloma Steering Committee

Understanding CAR T cell-tumor interactions: Paving the way for successful clinical outcomes

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