Identification and Validation of Predictive Biomarkers to CD19- and BCMA-Specific CAR T-Cell Responses in CAR T-Cell Precursors

Wang, Meng; Pruteanu, Iulian; Cohen, Adam D.; Garfall, Alfred L.; Milone, Michael C.; Tian, Lifeng; Gonzalez, Vanessa; Gill, Saar; Frey, Noelle V.; Barrett, David M.; Ruella, Marco; Lacey, Simon F.; Svoboda, Jakub; Chong, Elise A.; Fraietta, Joseph A.; Davis, Megan M.; Nasta, Sunita; Levine, Bruce L.; Siegel, Don L.; Maude, Shannon L.; Schuster, Stephen J.; Stadtmauer, Edward A.; Grupp, Stephan A.; Porter, David; June, Carl H.; Melenhorst, J. Joseph

doi:10.1182/blood-2019-122513

Cited by 17 publications

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“…There is increasing evidence that the heterogeneity of T-cell subsets in the apheresis product explains part of the variability of the activity of the CAR T cells infused to patients in clinical trials. First, several BCMA CAR T-cell studies show that patients with MM with a high frequency of early memory T cells in the leukapheresis product experience a higher response rate and superior peak CAR T-cell expansion when compared with patients with a low frequency of these cells (9,27,65,66). Similarly, the presence of early memory T cells in the leukapheresis product was correlated with response in patients with chronic lymphocytic leukemia (CLL), ALL, and lymphoma treated with CD19 CAR T cells (65,67,68).…”

Section: Baseline T-cell Characteristicsmentioning

confidence: 99%

“…First, several BCMA CAR T-cell studies show that patients with MM with a high frequency of early memory T cells in the leukapheresis product experience a higher response rate and superior peak CAR T-cell expansion when compared with patients with a low frequency of these cells (9,27,65,66). Similarly, the presence of early memory T cells in the leukapheresis product was correlated with response in patients with chronic lymphocytic leukemia (CLL), ALL, and lymphoma treated with CD19 CAR T cells (65,67,68). These findings can be explained by the ability of T cells with memory properties to undergo self-renewal and by their superior proliferative response compared with more differentiated T cells (69).…”

Section: Baseline T-cell Characteristicsmentioning

confidence: 99%

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Determinants of Response and Mechanisms of Resistance of CAR T-cell Therapy in Multiple Myeloma

Donk

Themeli

Usmani

2021

Blood Cancer Discovery

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B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cells have substantial therapeutic potential in multiple myeloma (MM), but most patients eventually relapse. Determinants of response and mechanisms of resistance are most likely multifactorial and include MM-related factors, premanufacturing T-cell characteristics, CAR T-cell-related features, and several components of the immunosuppressive microenvironment. Efforts to improve the potency and safety of CAR T-cell therapy include optimizing CAR design, combinatorial approaches to enhance persistence and activity, treatment of less heavily pretreated patients, and dual-antigen targeting to prevent antigen escape. We expect that these rationally designed strategies will contribute to further improvement in the clinical outcome of patients with MM.Significance: Although BCMA-specific CAR T-cell therapies are highly effective in heavily pretreated patients with MM, there has been, until now, no indication of a plateau in the survival curves. In this review, we provide an overview of the determinants of response and the mechanisms that contribute to the development of treatment failure after initial remission (acquired resistance). A better understanding of these mechanisms, underlying lack of disease response, and acquired resistance may lead to further improvements in the effectiveness of CAR T-cell therapy. iNtRODUctiONAlthough the introduction of new anti-multiple myeloma (MM) agents has markedly improved the survival of patients with MM, there is an unmet need for new drugs for patients who develop resistance to immunomodulatory drugs (IMiD), proteasome inhibitors (PI), and CD38-targeting antibodies (triple-class refractory disease), which carries a poor prognosis (1). Also, newly diagnosed patients with high-risk disease [e.g., presence of del(17p), t(4;14), or t(14;16)] or suboptimal response have an impaired outcome, and these patients may benefit from the incorporation of new drugs with novel mechanisms of action in first-line regimens.A promising new strategy is the reprogramming of T cells to target MM cells by introducing genes encoding chimeric antigen receptors (CAR). CARs are fusion proteins, combining an antigen-recognition moiety [commonly a monoclonal antibody-derived single-chain variable fragment (scFv), but other formats such as natural ligands are also possible; ref.2] with a T-cell activation domain, typically CD3ζ. These two parts are connected via an extracellular spacer region (hinge) and a transmembrane-spanning element. Second-generation CARs incorporating a costimulatory domain, such as CD28, 4-1BB, OX40, or ICOS, into the CAR endodomain result in enhanced antitumor activity of the modified T cells compared with first-generation CARs without such domain (Fig. 1; ref. 3). Importantly, CAR T cells eliminate tumor cells in a non-major histocompatibility complex (MHC)restricted manner.Most CAR T-cell products, currently evaluated in clinical trials for patients with MM, target B-cell maturation antigen (BCMA), which is...

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Section: Baseline T-cell Characteristicsmentioning

confidence: 99%

Section: Baseline T-cell Characteristicsmentioning

confidence: 99%

Determinants of Response and Mechanisms of Resistance of CAR T-cell Therapy in Multiple Myeloma

Donk

Themeli

Usmani

2021

Blood Cancer Discovery

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“…As for baseline biomarkers, cytokines of the immune system such as IL2, IL-5, IL-7, TNF-a, among others; lactate de Lactate dehydrogenase (LDH) and CD9 cells, are widely used. Meanwhile, for CAR-T cell function, the following biomarkers have been proposed: CD45RA, CD45RO, CD62L, CCR7, CD27, CD28 (differentiation markers), CD25, CD127, CD57, and CD137 (activation markers) ( Wang et al, 2019 ; Hong et al, 2021 ). Currently, there are no proven biomarkers that can be used to assess CAR-T cell exhaustion after infusion in patients.…”

Section: Immunotherapy a New Approach For Cancer Treatmentmentioning

confidence: 99%

Chimeric Antigen Receptor-T Cells: A Pharmaceutical Scope

et al. 2021

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Cancer is among the leading causes of death worldwide. Therefore, improving cancer therapeutic strategies using novel alternatives is a top priority on the contemporary scientific agenda. An example of such strategies is immunotherapy, which is based on teaching the immune system to recognize, attack, and kill malignant cancer cells. Several types of immunotherapies are currently used to treat cancer, including adoptive cell therapy (ACT). Chimeric Antigen Receptors therapy (CAR therapy) is a kind of ATC where autologous T cells are genetically engineered to express CARs (CAR-T cells) to specifically kill the tumor cells. CAR-T cell therapy is an opportunity to treat patients that have not responded to other first-line cancer treatments. Nowadays, this type of therapy still has many challenges to overcome to be considered as a first-line clinical treatment. This emerging technology is still classified as an advanced therapy from the pharmaceutical point of view, hence, for it to be applied it must firstly meet certain requirements demanded by the authority. For this reason, the aim of this review is to present a global vision of different immunotherapies and focus on CAR-T cell technology analyzing its elements, its history, and its challenges. Furthermore, analyzing the opportunity areas for CAR-T technology to become an affordable treatment modality taking the basic, clinical, and practical aspects into consideration.

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“…While in the first clinical trials, patients received CAR T-cell products comprising random compositions of T-cell subpopulations, evidence has been growing that efficiency and especially persistency can be enhanced through a tailored composition of T-cell subsets ( 150 ). Further, it has been demonstrated that enrichment of non-cycling, non-activated early memory CD8 + T-cells and CD4 + T-cells with early memory features in pre-manufacturing cells is a predictive biomarker of response to BCMA CAR T-cells in MM patients ( 151 ). On this basis, various approaches are currently investigated clinically for treatment with BCMA CAR T-cells: For example, the CD4 + /CD8 + ratio is adjusted to 1:1, before gene transfer in the JCARH125 product (NCT03430011) ( 55 ) or after gene transfer in the FCARH143 product (NCT03338972) ( 58 ), to avoid heterogeneity of the therapeutic agent between patients and to enable enhanced potency through optimized CD4 + CAR T-cell help to the CD8 + CAR T-cells ( 150 ).…”

Section: Selection Of Defined T-cell Subpopulationsmentioning

confidence: 99%

CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions

et al. 2020

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Despite recent therapeutic advances, the prognosis of multiple myeloma (MM) patients remains poor. Thus, new strategies to improve outcomes are imperative. Chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape of B-cell malignancies, providing a potentially curative option for patients who are refractory to standard treatment. Long-term remissions achieved in patients with acute lymphoblastic leukemia and Non-Hodgkin Lymphoma encouraged its further development in MM. B-cell maturation antigen (BCMA)-targeted CAR T-cells have established outstanding results in heavily pre-treated patients. However, several other antigens such as SLAMF7 and CD44v6 are currently under investigation with promising results. Idecabtagene vicleucel is expected to be approved soon for clinical use. Unfortunately, relapses after CAR T-cell infusion have been reported. Hence, understanding the underlying mechanisms of resistance is essential to promote prevention strategies and to enhance CAR T-cell efficacy. In this review we provide an update of the most recent clinical and pre-clinical data and we elucidate both, the potential and the challenges of CAR T-cell therapy in the future.

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Identification and Validation of Predictive Biomarkers to CD19- and BCMA-Specific CAR T-Cell Responses in CAR T-Cell Precursors

Cited by 17 publications

References 0 publications

Determinants of Response and Mechanisms of Resistance of CAR T-cell Therapy in Multiple Myeloma

Determinants of Response and Mechanisms of Resistance of CAR T-cell Therapy in Multiple Myeloma

Chimeric Antigen Receptor-T Cells: A Pharmaceutical Scope

CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions

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