Allogeneic CD20‐targeted γδ T cells exhibit innate and adaptive antitumor activities in preclinical B‐cell lymphoma models

Nishimoto, Kevin; Barca, Taylor; Azameera, Aruna; Makkouk, Amani; Romero, Jason M.; Bai, Lu; Brodey, Mary M.; Kennedy-Wilde, Jackie; Shao, Hui; Papaioannou, Stephanie; Doan, A.N.; Masri, Cynthia; Hoang, Ngoc T.; Tessman, Hayden; Ramanathan, Vidhya Dhevi; Giner‐Rubio, Ana; Delfino, Frank J.; Sharma, Kriti Sen; Bray, Kevin; Hoopes, Matthew I.; Satpayev, Daulet; Sengupta, Ranjita; Herrman, Marissa; Abbot, Stewart; Aftab, Blake T.; An, Zili; Panuganti, Swapna; Hayes, Sandra M.

doi:10.1002/cti2.1373

Cited by 72 publications

(57 citation statements)

References 65 publications

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“…Critically, daily-infused IL-15 enabled CD123CAR-DOTs to sustain their anti-leukemic activity for more than 70 days, even after AML re-challenge. These results are in agreement with recent elegant publications showing CAR-Vδ1 T-cell efficacy and the adjuvant effect of IL-15 in B-cell lymphoma and hepatocellular carcinoma models 12,46 . Only the clinical setting can establish the real benefit of IL-15 co-administration (potentially with an inducible “switch off” system) with CD123CAR-DOTs.…”

Section: Discussionsupporting

confidence: 93%

“…1E), and the upregulation of a NK-associated cytotoxicity machinery (including DNAM-1, NKp30 and NKp44) 10,14 that may be critical in the advent of CAR antigen loss as previously observed with CD19 in B-ALL 6 . Importantly, this enhanced NK-like cytotoxicity is also an advantage over other  T cell-based products being developed for adoptive immunotherapy of cancer [7][8][9]12,46 . On the other hand, in comparison with NK cells, which obviously share such activating NK-cell receptors, DOTs offer as key advantages 7,8,53 the previously documented 11 absence of inhibitory KIRs, namely KIR2DL1, KIR2DL2, KIR2DL4, KIR2DL5A and KIR3DL1, and the additional input of TCR-dependent activation and expansion (up to very high yields as reported 10,14 ).…”

Section: Discussionmentioning

confidence: 98%

“…In particular, MHC/HLA-independent T cells have emerged as a promising candidate based on their potent cytotoxic activity and release of cytokines stimulating and recruiting other immune cells to the tumor site [7][8][9] . While the low abundance of  T cells in the human peripheral blood (PB) has hindered their clinical application, recent advances in protocol development have enabled their ex vivo expansion to large numbers [10][11][12][13] . In particular, we have characterized Delta One T (DOT) cells, a Vδ1 T cell-enriched cellular product expressing enhanced levels of natural cytotoxicity receptors (NCRs), and demonstrated that they constitute a safe and efficient effector platform to eliminate cancer cells in in vitro and in vivo pre-clinical models of solid and hematological malignancies 10 , most notably acute myeloid leukemia (AML) 14 .…”

Section: Introductionmentioning

confidence: 99%

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Generation and proof-of-concept for allogeneic CD123 CAR-Delta One T (DOT) cells in Acute Myeloid Leukemia

Martinez

Tirado

Mensurado

et al. 2022

Preprint

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Chimeric Antigen Receptor (CAR)-T cells have emerged as a breakthrough treatment for relapse/refractory (r/r) hematological tumors, showing impressive complete remission rates in B-cell malignancies. However, around 50% of the patients relapse before 1-year post-treatment. T-cell fitness is critical to prolong the persistence and activity of the adoptively transferred product. Allogeneic T cells from healthy donors are less dysfunctional or exhausted than autologous patient-derived T cells, enabling a very attractive and cost-effective off-the-shelf therapy option. In this context, Delta One T cells (DOTs), a recently described cellular product based on MHC/HLA-independent Vd1+ gd T cells generated from the peripheral blood of healthy donors, represent a robust platform of allogeneic effector T cells. Here we generated and pre-clinically validated 4-1BB-based CAR-DOTs directed against the IL-3a; chain receptor (CD123), a target antigen widely expressed on acute myeloid leukemia (AML) blasts. CD123CAR-DOTs showed vigorous, superior to control DOTs, cytotoxicity against AML cell lines and primary samples both in vitro and in vivo. Continuous administration of IL-15 supported the long-term persistence of a single-dose CD123CAR-DOTs in patient-derived xenograft models, sustaining their anti-leukemic efficacy as demonstrated in a re-challenge assay in vivo. Our results provide proof-of-concept for an allogeneic next-generation therapy based on CD123CAR-DOTs for r/r AML patients.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Generation and proof-of-concept for allogeneic CD123 CAR-Delta One T (DOT) cells in Acute Myeloid Leukemia

Martinez

Tirado

Mensurado

et al. 2022

Preprint

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“…Following the United States Food and Drug Administration (US FDA) approval for ADI-01 in the year 2020, an allogenic CAR γδ T cell therapy targeting CD20 protein was manufactured at clinical scale. As observed in a preclinical study with B-cell malignancies, CAR γδ T cell therapy generated an innate and adaptive anti-tumor immune response but no xenogeneic graft-versus-host disease ( 143 ). This CD20 CAR γδ T cell therapy is now in a phase I clinical trial ( ).…”

Section: γδ T Cell-based Immunotherapy: Missing Links and Unexplored ...mentioning

confidence: 94%

Contemplating Dichotomous Nature of Gamma Delta T Cells for Immunotherapy

2022

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γδ T cells are unconventional T cells, distinguished from αβ T cells in a number of functional properties. Being small in number compared to αβ T cells, γδ T cells have surprised us with their pleiotropic roles in various diseases. γδ T cells are ambiguous in nature as they can produce a number of cytokines depending on the (micro) environmental cues and engage different immune response mechanisms, mainly due to their epigenetic plasticity. Depending on the disease condition, γδ T cells contribute to beneficial or detrimental response. In this review, we thus discuss the dichotomous nature of γδ T cells in cancer, neuroimmunology and infectious diseases. We shed light on the importance of equal consideration for systems immunology and personalized approaches, as exemplified by changes in metabolic requirements. While providing the status of immunotherapy, we will assess the metabolic (and other) considerations for better outcome of γδ T cell-based treatments.

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“…Their multimodal approach to cell destruction makes γδ T cells good candidates for CAR engineering. An anti-CD20 allo-CAR made from γδ T cells has demonstrated manufacturing feasibility and improved cytotoxic activity over conventional CAR-T cells in a preclinical model of B-cell lymphoma ( 28 ), which has subsequently led to a Phase 1 trial in humans (NCT04735471).…”

Section: Introductionmentioning

confidence: 99%

Custom CARs: Leveraging the Adaptability of Allogeneic CAR Therapies to Address Current Challenges in Relapsed/Refractory DLBCL

Jeyakumar

Smith

2022

Front. Immunol.

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Cellular therapies have transformed the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), which typically does not respond well to salvage chemotherapy. Recently, approximately 40% of r/r DLBCL patients across three different trials achieved a complete remission at 1 year after receiving treatment with autologous chimeric antigen receptor (CAR) T cells (auto-CARs). These successes have prompted studies of auto-CARs in second-line settings, in which axicabtagene ciloleucel and lisocabtagene maraleucel both showed improved event-free survival over autologous hematopoietic cell transplantation (AHCT). While encouraging, this data also highlights that 60% of patients relapse or progress following treatment with auto-CARs. Individual disease characteristics and logistical challenges of cell engineering also limit patients’ eligibility for auto-CARs. Allogeneic CAR T cells (allo-CARs) may address some of these limitations as they may mitigate delays associated with auto-CARs, thereby reducing the need for bridging chemotherapies and increasing availability of cellular products for patients with aggressive lymphomas. By being sourced from healthy donors who have never been exposed to cytotoxic chemotherapy, allo-CARs can be created from T cells with better fitness. Allo-CARs made from specific cellular subsets (e.g., stem cell memory or naïve/early memory T cells) may also have increased efficacy and long-term persistence. Additionally, allo-CARs have been successfully created from other cell types, including natural killer cells, gamma-delta T-cells and induced pluripotent stem cells. These cell types can be engineered to target viral antigens, enabling precision targeting of virally driven DLBCL. As allogeneic donor cells can be banked and cryopreserved in batches, they can be made more readily available, potentially reducing logistical hurdles and costs compared to engineering auto-CARs. This may ultimately create a more sustainable platform for cell therapies. Challenges with allo-CARs that will need to be addressed include graft versus host disease, alloimmunization, potentially decreased persistence relative to auto-CARs, and antigen escape. In short, the adaptability of allo-CARs makes them ideal for treating patients with r/r DLBCL who have progressed through standard chemotherapy, AHCT, or auto-CARs. Here, we review the published literature on patients with r/r DLBCL treated with allogeneic CAR products manufactured from various cell types as well as forthcoming allogeneic CAR technologies.

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Allogeneic CD20‐targeted γδ T cells exhibit innate and adaptive antitumor activities in preclinical B‐cell lymphoma models

Cited by 72 publications

References 65 publications

Generation and proof-of-concept for allogeneic CD123 CAR-Delta One T (DOT) cells in Acute Myeloid Leukemia

Generation and proof-of-concept for allogeneic CD123 CAR-Delta One T (DOT) cells in Acute Myeloid Leukemia

Contemplating Dichotomous Nature of Gamma Delta T Cells for Immunotherapy

Custom CARs: Leveraging the Adaptability of Allogeneic CAR Therapies to Address Current Challenges in Relapsed/Refractory DLBCL

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