Immunogenicity of CAR-T Cell Therapeutics: Evidence, Mechanism and Mitigation

Khan, Aalia; Chowdhury, Ambalika; Karulkar, Atharva; Jaiswal, Ankesh Kumar; Banik, Ankit; Asija, Sweety; Purwar, Rahul

doi:10.3389/fimmu.2022.886546

Cited by 50 publications

(30 citation statements)

References 107 publications

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“…Conversely, two CAR T cell cancer medications, which are currently in clinical use, produce an ADA response without a negative impact. Research with Yescarta and Kymriah, products currently approved for use in patients with large B cell lymphoma and acute lymphoblastic anemia respectively, has demonstrated a lack of correlation between anti-CAR antibody level and expansion and persistence of the CAR T cells ( 28 , 43 – 45 ). Nevertheless, the impact of ADA responses can be variable, and therefore determining the relative immunogenicity in preclinical models is paramount to developing a safe and effective therapy ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

Development of an anti-CAR antibody response in SIV-infected rhesus macaques treated with CD4-MBL CAR/CXCR5 T cells

et al. 2022

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T cells expressing a simian immunodeficiency (SIV)-specific chimeric antigen receptor (CAR) and the follicular homing molecule, CXCR5, were infused into antiretroviral therapy (ART) suppressed, SIV-infected rhesus macaques to assess their ability to localize to the lymphoid follicle and control the virus upon ART interruption. While the cells showed evidence of functionality, they failed to persist in the animals beyond 28 days. Development of anti-CAR antibodies could be responsible for the lack of persistence. Potential antigenic sites on the anti-SIV CAR used in these studies included domains 1 and 2 of CD4, the carbohydrate recognition domain (CRD) of mannose-binding lectin (MBL), and an extracellular domain of the costimulatory molecule, CD28, along with short linker sequences. Using a flow cytometry based assay and target cells expressing the CAR/CXCR5 construct, we examined the serum of the CD4-MBL CAR/CXCR5-T cell treated animals to determine that the animals had developed an anti-CAR antibody response after infusion. Binding sites for the anti-CAR antibodies were identified by using alternative CARs transduced into target cells and by preincubation of the target cells with a CD4 blocking antibody. All of the treated animals developed antibodies in their serum that bound to CD4-MBL CAR/CXCR5 T cells and the majority were capable of inducing an ADCC response. The CD4 antibody-blocking assay suggests that the dominant immunogenic components of this CAR are the CD4 domains with a possible additional site of the CD28 domain with its linker. This study shows that an anti-drug antibody (ADA) response can occur even when using self-proteins, likely due to novel epitopes created by abridged self-proteins and/or the self-domain of the CAR connection to a small non-self linker. While in our study, there was no statistically significant correlation between the ADA response and the persistence of the CD4-MBL CAR/CXCR5-T cells in rhesus macaques, these findings suggest that the development of an ADA response could impact the long-term persistence of self-based CAR immunotherapies.

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Section: Discussionmentioning

confidence: 99%

Development of an anti-CAR antibody response in SIV-infected rhesus macaques treated with CD4-MBL CAR/CXCR5 T cells

et al. 2022

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“…Importantly, compared to the rest of the CD20-specific CARs, the 2F2-CAR design offers yet another advantage, namely it is fully human in sequence, which may reduce the chance of CAR T cell-associated toxicities and increase the persistence/efficacy of the CAR T cell product. The efficacy of the reference FMC63-based CD19-specific CAR, which has an antigen-recognition module of a mouse origin, is not known to be affected by the human anti-mouse antibody (HAMA) response, yet this may occur in the context of other scFvs and include T cell responses to foreign peptides [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative Pre-Clinical Analysis of CD20-Specific CAR T Cells Encompassing 1F5-, Leu16-, and 2F2-Based Antigen-Recognition Moieties

Belovezhets

Kulemzin

Volkova

et al. 2023

IJMS

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Over the past decade, CAR T cell therapy for patients with B cell malignancies has evolved from an experimental technique to a clinically feasible option. To date, four CAR T cell products specific for a B cell surface marker, CD19, have been approved by the FDA. Despite the spectacular rates of complete remission in r/r ALL and NHL patients, a significant proportion of patients still relapse, frequently with the CD19 low/negative tumor phenotype. To address this issue, additional B cell surface molecules such as CD20 were proposed as targets for CAR T cells. Here, we performed a side-by-side comparison of the activity of CD20-specific CAR T cells based on the antigen-recognition modules derived from the murine antibodies, 1F5 and Leu16, and from the human antibody, 2F2. Whereas CD20-specific CAR T cells differed from CD19-specific CAR T cells in terms of subpopulation composition and cytokine secretion, they displayed similar in vitro and in vivo potency.

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“…The original Phase 1 study of LCAR-B38M (the precursor to cilta-cel) also demonstrated higher rates of relapse among patients who developed ADAs ( 14 ). As a caveat, studies of CAR-T therapies across hematologic malignancies have yielded mixed results regarding whether ADAs are always clinically relevant in terms of CAR-T efficacy ( 52 , 53 ).…”

Section: Better Mileage: Longer Duration Of Responsesmentioning

confidence: 99%

Innovation in BCMA CAR-T therapy: Building beyond the Model T

2022

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Autologous chimeric antigen receptor T-cell (CAR-T) therapies targeting B-cell maturation antigen (BCMA) have revolutionized the field of multiple myeloma in the same way that the Ford Model T revolutionized the original CAR world a century ago. However, we are only beginning to understand how to improve the efficacy and usability of these cellular therapies. In this review, we explore three automotive analogies for innovation with BCMA CAR-T therapies: stronger engines, better mileage, and hassle-free delivery. Firstly, we can build stronger engines in terms of BCMA targeting: improved antigen binding, tools to modulate antigen density, and armoring to better reach the antigen itself. Secondly, we can improve “mileage” in terms of response durability through ex vivo CAR design and in vivo immune manipulation. Thirdly, we can implement hassle-free delivery through rapid manufacturing protocols and off-the-shelf products. Just as the Model T set a benchmark for car manufacturing over 100 years ago, idecabtagene vicleucel and ciltacabtagene autoleucel have now set the starting point for BCMA CAR-T therapy with their approvals. As with any emerging technology, whether automotive or cellular, the best in innovation and optimization is yet to come.

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Immunogenicity of CAR-T Cell Therapeutics: Evidence, Mechanism and Mitigation

Cited by 50 publications

References 107 publications

Development of an anti-CAR antibody response in SIV-infected rhesus macaques treated with CD4-MBL CAR/CXCR5 T cells

Development of an anti-CAR antibody response in SIV-infected rhesus macaques treated with CD4-MBL CAR/CXCR5 T cells

Comparative Pre-Clinical Analysis of CD20-Specific CAR T Cells Encompassing 1F5-, Leu16-, and 2F2-Based Antigen-Recognition Moieties

Innovation in BCMA CAR-T therapy: Building beyond the Model T

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