Lymphodepletion strategies to potentiate adoptive T-cell immunotherapy – what are we doing; where are we going?

Bechman, Natasha; Maher, John

doi:10.1080/14712598.2021.1857361

Cited by 35 publications

(31 citation statements)

References 103 publications

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“…9, 114). Although lymphodepletion with fludarabine/ cyclophosphamide is effective in patients with MM and other hematologic malignancies, this lymphodepleting regimen is also associated with toxicity, such as long-lasting cytopenias and infections (119). Therefore, further investigations are warranted to define the most optimal lymphodepleting conditioning regimen prior to CAR T-cell immunotherapy in MM.…”

Section: Lymphodepleting Conditioning Regimenmentioning

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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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: Lymphodepleting Conditioning Regimenmentioning

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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“…In recent decades, chimeric antigen receptor (CAR) T-cell immunotherapy emerged as another exciting treatment modality for high-risk relapsed/refractory (r/r) CLL patients with resistance to other treatment modalities, complex cytogenetics, and/or TP53 abnormalities [ 5 ], who would otherwise have dismal prognoses. Generally, a lymphodepleting regimen is applied prior to CAR T-cell infusion to potentiate the clinical effect [ 6 ]. CAR T cells are T lymphocytes that have been genetically modified to express CAR on their surface.…”

Section: Introductionmentioning

confidence: 99%

Current State of CAR T-Cell Therapy in Chronic Lymphocytic Leukemia

Mančíková

Šmída

2021

IJMS

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Chimeric antigen receptor (CAR) T-cell therapy has already achieved remarkable remissions in some difficult-to-treat patients with B-cell malignancies. Although the clinical experience in chronic lymphocytic leukemia (CLL) patients is limited, the proportion of remissions reached in this disease is clearly the lowest from the spectrum of B-cell tumors. In this review, we discuss the antigenic targets exploited in CLL CAR-T therapy, the determinants of favorable responses, as well as the mechanisms of treatment failure specific to this disease.

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“…The central purpose of all these strategies is to stimulate a potent, viable, tumor-specific, T-cell response with a retained in vivo expansion capability [ 37 ]. While therapeutic approaches using engineered T-cells with chimeric tumor associated antigens (CAR-T cells) are growing in popularity [ 38 ], several other bulk expansion strategies such as using tumor infiltrating lymphocytes (TILs) ex vivo expanded with IL-2 [ 39 ], or lymphodepletion [ 40 ] followed by autologous transfer of activated T cells were also extensively tested in clinical trials. A major challenge with the bulk expansion strategies includes the lack of tumor antigen specificity [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Ex Vivo High Salt Activated Tumor-Primed CD4+T Lymphocytes Exert a Potent Anti-Cancer Response

Tiriveedhi

Ivy

Myles

et al. 2021

Cancers

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Cell based immunotherapy is rapidly emerging as a promising cancer treatment. A modest increase in salt (sodium chloride) concentration in immune cell cultures is known to induce inflammatory phenotypic differentiation. In our current study, we analyzed the ability of salt treatment to induce ex vivo expansion of tumor-primed CD4 (cluster of differentiation 4)+T cells to an effector phenotype. CD4+T cells were isolated using immunomagnetic beads from draining lymph nodes and spleens from tumor bearing C57Bl/6 mice, 28 days post-injection of Py230 syngeneic breast cancer cells. CD4+T cells from non-tumor bearing mice were isolated from splenocytes of 12-week-old C57Bl/6 mice. These CD4+T cells were expanded ex vivo with five stimulation cycles, and each cycle comprised of treatment with high salt (Δ0.035 M NaCl) or equimolar mannitol controls along with anti-CD3/CD28 monoclonal antibodies for the first 3 days, followed by the addition of interleukin (IL)-2/IL-7 cytokines and heat killed Py230 for 4 days. Ex vivo high salt treatment induced a two-fold higher Th1 (T helper type 1) expansion and four-fold higher Th17 expansion compared to equimolar mannitol treatment. Importantly, the high salt expanded CD4+T cells retained tumor-specificity, as demonstrated by higher in vitro cytotoxicity against Py230 breast cancer cells and reduced in vivo syngeneic tumor growth. Metabolic studies revealed that high salt treatment enhanced the glycolytic reserve and basal mitochondrial oxidation of CD4+T cells, suggesting a role of high salt in enhanced pro-growth anabolic metabolism needed for inflammatory differentiation. Mechanistic studies demonstrated that the high salt induced switch to the effector phenotype was mediated by tonicity-dependent transcription factor, TonEBP/NFAT5. Using a transgenic murine model, we demonstrated that CD4 specific TonEBP/NFAT5 knock out (CD4cre/creNFAT5flox/flox) abrogated the induction of the effector phenotype and anti-tumor efficiency of CD4+T cells following high salt treatment. Taken together, our data suggest that high salt-mediated ex vivo expansion of tumor-primed CD4+T cells could induce effective tumor specific anti-cancer responses, which may have a novel cell-based cancer immunotherapeutic application.

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Lymphodepletion strategies to potentiate adoptive T-cell immunotherapy – what are we doing; where are we going?

Cited by 35 publications

References 103 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

Current State of CAR T-Cell Therapy in Chronic Lymphocytic Leukemia

Ex Vivo High Salt Activated Tumor-Primed CD4+T Lymphocytes Exert a Potent Anti-Cancer Response

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