CARs versus BiTEs: A Comparison between T Cell–Redirection Strategies for Cancer Treatment

Slaney, Clare Y.; Wang, Pin; Darcy, Phillip K.; Kershaw, Michael H.

doi:10.1158/2159-8290.cd-18-0297

Cited by 188 publications

(168 citation statements)

References 113 publications

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“…Unlike CAR T-cell therapies, bispecific antibody constructs themselves do not proliferate but rather act by inducing expansion of antigenexperienced T cells. Although it is unclear how to directly compare the immune expansion capability of bispecific antibody constructs and CAR T-cell therapies, it has been noted that the expansion of antigen-experienced T cells by bispecific antibody constructs can be order of magnitudes lower than the self-expansion of CAR T-cell therapies [81]. Because the resolution of malignant disease could require continued action of T cells over prolonged time periods, differences in T-cell expansion and persistence between bispecific antibody constructs and CAR T-cell therapies could lead to differences in durability of remission, though there is currently insufficient clinical data for BCMAtargeted therapies to date to make direct comparisons [81].…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

et al. 2020

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Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.

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Section: Discussion and Future Perspectivesmentioning

confidence: 99%

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

et al. 2020

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“…Given their potential for enhancing T-cell activation, agonistic antibodies targeting costimulatory receptors (e.g., CD137/4-1BB, OX40) are also under investigation (41). domain, to bypass major histocompatibility complex (MHC)-dependent binding to TAAs, and intracellular signaling domains for T-cell activation/costimulation (43). T-cell activation is initiated following immune synapse (IS) formation, which facilitates lytic granulemediated apoptosis of the target cell.…”

Section: Disease Progressionmentioning

confidence: 99%

How to Train Your T Cells: Overcoming Immune Dysfunction in Multiple Myeloma

Cohen

Raje

Fowler

et al. 2020

Clinical Cancer Research

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The progression of multiple myeloma, a hematologic malignancy characterized by unregulated plasma cell growth, is associated with increasing innate and adaptive immune system dysfunction, notably in the T-cell repertoire. Although treatment advances in multiple myeloma have led to deeper and more durable clinical responses, the disease remains incurable for most patients. Therapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and activating the host immune system have recently shown promise in multiple myeloma, particularly in the relapsed and/or refractory disease setting. As the efficacy of T-cell-dependent immuno-oncology therapy is likely affected by the health of the endogenous T-cell repertoire, these therapies may also provide benefit in alternate treatment settings (e.g., precursor disease; after stem cell transplantation). This review describes T-cell-associated changes during the evolution of multiple myelo-ma and provides an overview of T-cell-dependent immunooncology approaches under investigation. Vaccine and checkpoint inhibitor interventions are being explored across the multiple myeloma disease continuum; treatment modalities that redirect patient T cells to elicit an anti-multiple myeloma response, namely, chimeric antigen receptor (CAR) T cells and bispecific antibodies [including BiTE (bispecific T-cell engager) molecules], have been primarily evaluated to date in the relapsed and/or refractory disease setting. CAR T cells and bispecific antibodies/antibody constructs directed against B-cell maturation antigen have generated excitement, with clinical data demonstrating deep responses. An increased understanding of the complex interplay between the immune system and multiple myeloma throughout the disease course will aid in maximizing the potential for T-cell-dependent immuno-oncology strategies in multiple myeloma.

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“…As such, several anticancer drugs have been developed that specifically target these enzymes. More recently, non-cancer cells infiltrating tissues are attracting attention as potential therapeutic targets [17][18][19]. In this approach, drugs target non-cancer cells that are in close proximity to cancerous cells rather than targeting tumor cells directly.…”

Section: Current Status Of Drug Development Targeting the Stroma Of Cmentioning

confidence: 99%

Search for drug discovery targets focusing on cancer stroma

Kamada

2019

Translational and Regulatory Sciences

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In recent years, it has become clear that the interstitial tissue structure varies markedly between the normal healthy state and various disease states. Focusing on differences in interstitial structure is expected to lead to the discovery of new targets for drugs. Considerable attention is currently focused on approaches that utilize organoids. The organoids retain the structure of the tissue, thereby facilitating identification of drugs that target interstitial tissues including neovascular vessels. Furthermore, protein expression analysis techniques have been developed that focus on the tissue structure based on an approach using chemical proteomics. In this mini-review, we will summarize the latest technological innovations aimed at identifying target molecules that are useful for the development of biopharmaceuticals, including antibody drugs.

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CARs versus BiTEs: A Comparison between T Cell–Redirection Strategies for Cancer Treatment

Cited by 188 publications

References 113 publications

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

How to Train Your T Cells: Overcoming Immune Dysfunction in Multiple Myeloma

Search for drug discovery targets focusing on cancer stroma

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