bims-adocet Biomed News
on Adoptive cell therapy
Issue of 2024–09–08
eight papers selected by
Shani Kassia Lyskov, Tel Aviv University
  1. Fratricide-resistant CD7-CAR T cells in T-ALL.
  2. Multi-armored allogeneic MUC1 CAR T cells enhance efficacy and safety in triple-negative breast cancer.
  3. Rab5 Overcomes CAR T Cell Dysfunction Induced by Tumor-Mediated CAR Capture.
  4. Targeting the membrane-proximal C2-set domain of CD33 for improved CAR T cell therapy.
  5. Engineered NKG2C + NK-like T cells exhibit superior antitumor efficacy while mitigating cytokine release syndrome.
  6. PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis.
  7. CD4+ tumor-infiltrating lymphocytes secreting T cell-engagers induce regression of autologous patient-derived non-small cell lung cancer xenografts.
  8. Local Radiation Enhances Systemic CAR T Cell Efficacy by Augmenting Antigen Cross-Presentation and T-cell Infiltration.
  1. Nat Med. 2024 Sep 03.
    Fratricide-resistant CD7-CAR T cells in T-ALL.
    Bernice L Z Oh, Noriko Shimasaki, Elaine Coustan-Smith, Esther Chan, Limei Poon, Shawn H R Lee, Frances Yeap, Lip Kun Tan, Louis Y A Chai, Nina Le Bert, Nicole Tan, Antonio Bertoletti, Siew Peng Chen, Francesca Del Bufalo, Marco Becilli, Franco Locatelli, Allen E J Yeoh, Dario Campana.
      T cell acute lymphoblastic leukemia (T-ALL) is difficult to treat when it relapses after therapy or is chemoresistant; the prognosis of patients with relapsed or refractory T-ALL is generally poor. We report a case series of 17 such patients who received autologous chimeric antigen receptor (CAR) T cells expressing an anti-CD7 CAR and an anti-CD7 protein expression blocker (PEBL), which prevented CAR T cell fratricide. Despite high leukemic burden and low CAR T cell dosing, 16 of the 17 patients attained minimal residual disease-negative complete remission within 1 month. The remaining patient had CD7- T-ALL cells before infusion, which persisted after infusion. Toxicities were mild: cytokine release syndrome grade 1 in ten patients and grade 2 in three patients; immune effector cell-associated neurotoxicity syndrome grade 1 in two patients. Eleven patients remained relapse-free (median follow-up, 15 months), including all nine patients who received an allotransplant. The first patient is in remission 55 months after infusion without further chemotherapy or transplantation; circulating CAR T cells were detectable for 2 years. T cells regenerating after lymphodepletion lacked CD7 expression, were polyclonal and responded to SARS-CoV-2 vaccination; CD7+ immune cells reemerged concomitantly with CAR T cell disappearance. In conclusion, autologous anti-CD7 PEBL-CAR T cells have powerful antileukemic activity and are potentially an effective option for the treatment of T-ALL.
    DOI:  https://doi.org/10.1038/s41591-024-03228-8
  2. Sci Adv. 2024 Aug 30. 10(35): eadn9857
    Multi-armored allogeneic MUC1 CAR T cells enhance efficacy and safety in triple-negative breast cancer.
    Piril Erler, Tomasz Kurcon, Hana Cho, Jordan Skinner, Chantel Dixon, Steven Grudman, Sandra Rozlan, Emilie Dessez, Ben Mumford, Sumin Jo, Alex Boyne, Alexandre Juillerat, Philippe Duchateau, Laurent Poirot, Beatriz Aranda-Orgilles.
      Solid tumors, such as triple-negative breast cancer (TNBC), are biologically complex due to cellular heterogeneity, lack of tumor-specific antigens, and an immunosuppressive tumor microenvironment (TME). These challenges restrain chimeric antigen receptor (CAR) T cell efficacy, underlining the importance of armoring. In solid cancers, a localized tumor mass allows alternative administration routes, such as intratumoral delivery with the potential to improve efficacy and safety but may compromise metastatic-site treatment. Using a multi-layered CAR T cell engineering strategy that allowed a synergy between attributes, we show enhanced cytotoxic activity of MUC1 CAR T cells armored with PD1KO, tumor-specific interleukin-12 release, and TGFBR2KO attributes catered towards the TNBC TME. Intratumoral treatment effectively reduced distant tumors, suggesting retention of antigen-recognition benefits at metastatic sites. Overall, we provide preclinical evidence of armored non-alloreactive MUC1 CAR T cells greatly reducing high TNBC tumor burden in a TGFB1- and PD-L1-rich TME both at local and distant sites while preserving safety.
    DOI:  https://doi.org/10.1126/sciadv.adn9857
  3. bioRxiv. 2024 Jul 26. pii: 2024.07.26.605334. [Epub ahead of print]
    Rab5 Overcomes CAR T Cell Dysfunction Induced by Tumor-Mediated CAR Capture.
    Meidi Gu, Edmund J Carvalho, Kaitlin A Read, David Padron Nardo, James L Riley.
      Continuous interaction between chimeric antigen receptor (CAR) T cell (CART) and tumors often result in CART dysfunction and tumor escape. We observed that tumors can take up CAR molecules, leaving CARTs without surface-expressed CARs and thus unable to kill tumors after prolonged exposure. Overexpression of Rab5 resulted in augmented clathrin-independent endocytosis, preventing loss of surface-expressed CARs, and enhanced CART activity. Interestingly, we observed membrane protrusions on the CART cell surface which disappeared after multiple tumor challenges. Rab5 maintained these protrusions after repeated tumor engagements and their presence correlated with effective tumor clearance, suggesting a link between endocytosis, membrane protrusions, and cytolytic activity. In vivo , Rab5-expressing CARTs demonstrated improved activity and were able to clear an otherwise refractory mesothelin-expressing solid cancer in humanized mice by maintaining CAR surface expression within the tumor. Thus, pairing Rab5 with CAR expression could improve the clinical efficacy of CART therapy. Highlights "CAR-jacking" occurs when surface CAR is internalized by target tumor cells.Rab5 overexpression prevents "CAR-jacking" and enhances CART function.Rab5 promotes CAR endocytic recycling and maintains membrane protrusions.Rab5-expressing CARTs exhibit enhanced therapeutic efficacy against solid tumors.
    DOI:  https://doi.org/10.1101/2024.07.26.605334
  4. Mol Ther Oncol. 2024 Sep 19. 32(3): 200854
    Targeting the membrane-proximal C2-set domain of CD33 for improved CAR T cell therapy.
    Salvatore Fiorenza, Sheryl Y T Lim, George S Laszlo, Erik L Kimble, Tinh-Doan Phi, Margaret C Lunn-Halbert, Delaney R Kirchmeier, Jenny Huo, Hans-Peter Kiem, Cameron J Turtle, Roland B Walter.
      Current CD33-targeted immunotherapies typically recognize the membrane-distal V-set domain of CD33. Here, we show that decreasing the distance between T cell and leukemia cell membrane increases the efficacy of CD33 chimeric antigen receptor (CAR) T cells. We therefore generated and optimized second-generation CAR constructs containing single-chain variable fragments from antibodies raised against the membrane-proximal C2-set domain, which bind CD33 regardless of whether the V-set domain is present (CD33PAN antibodies). CD33PAN CAR T cells resulted in efficient tumor clearance and improved survival of immunodeficient mice bearing human AML cell xenografts and, in an AML model with limited CD33 expression, forced escape of CD33neg leukemia. Compared to CD33V-set CAR T cells, CD33PAN CAR T cells showed greater in vitro and in vivo efficacy against several human AML cell lines with differing levels of CD33 without increased expression of exhaustion markers. CD33PAN moieties were detected at a higher frequency on human leukemic stem cells, and CD33PAN CAR T cells had greater in vitro efficacy against primary human AML cells. Together, our studies demonstrate improved efficacy with CAR T cells binding CD33 close to the cell membrane, providing the rationale to investigate CD33PAN CAR T cells further toward possible clinical application.
    Keywords:  AML; CAR; CD33; MT: Novel therapeutic targets and biomarker development Special Issue; T cells; acute myeloid leukemia; adoptive cell therapy; chimeric antigen receptor; immunotherapy; membrane proximity
    DOI:  https://doi.org/10.1016/j.omton.2024.200854
  5. bioRxiv. 2024 Aug 01. pii: 2024.07.16.603785. [Epub ahead of print]
    Engineered NKG2C + NK-like T cells exhibit superior antitumor efficacy while mitigating cytokine release syndrome.
    Kyle B Lupo, M Kazim Panjwani, Sanam Shahid, Rosa Sottile, Clara Lawry, Gabryelle Kolk, Theodota Kontopolous, Anthony F Daniyan, Smita S Chandran, Christopher A Klebanoff, Katharine C Hsu.
      Engineered T and NK cell therapies have widely been used to treat hematologic malignancies and solid tumors, with promising clinical results. Current chimeric antigen receptor (CAR) T cell therapeutics have, however, been associated with treatment-related adverse events such as cytokine release syndrome (CRS) and are prone to immunologic exhaustion. CAR-NK therapeutics, while not associated with CRS, have limited in vivo persistence. We now demonstrate that an NK-like TCRαβ + CD8 T cell subset, identified and expanded ex vivo through its expression of the activating receptor NKG2C (NKG2C + NK-like T cells), can be transduced to express a second-generation CD19 CAR (1928z), resulting in superior tumor clearance, longer persistence and decreased exhaustion compared to conventional 1928z CAR + CD8 T cells and 1928z CAR+ NK cells. Moreover, CAR-modified NKG2C + NK-like T cells resulted in significantly reduced CRS compared to conventional CAR + CD8 T cells. Similarly, NKG2C + NK-like T cells engineered with a TCR targeting the NY-ESO-1 antigen exhibit robust tumor control and minimal exhaustion compared to TCR-engineered conventional CD8 T cells. These data establish NKG2C + NK-like T cells as a robust platform for cell engineering, and offer a safer, more durable alternative to conventional CAR-T and CAR-NK therapies.
    DOI:  https://doi.org/10.1101/2024.07.16.603785
  6. Immunity. 2024 Aug 22. pii: S1074-7613(24)00376-5. [Epub ahead of print]
    PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis.
    Yu Ping, Jiqi Shan, Haiming Qin, Feng Li, Jiao Qu, Ru Guo, Dong Han, Wei Jing, Yaqing Liu, Jinyan Liu, Zhangnan Liu, Jieyao Li, Dongli Yue, Feng Wang, Liping Wang, Bin Zhang, Bo Huang, Yi Zhang.
      The tumor microenvironment (TME) promotes metabolic reprogramming and dysfunction in immune cells. Here, we examined the impact of the TME on phospholipid metabolism in CD8+ T cells. In lung cancer, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were lower in intratumoral CD8+ T cells than in circulating CD8+ T cells. Intratumoral CD8+ T cells exhibited decreased expression of phospholipid phosphatase 1 (PLPP1), which catalyzes PE and PC synthesis. T cell-specific deletion of Plpp1 impaired antitumor immunity and promoted T cell death by ferroptosis. Unsaturated fatty acids in the TME stimulated ferroptosis of Plpp1-/- CD8+ T cells. Mechanistically, programmed death-1 (PD-1) signaling in CD8+ T cells induced GATA1 binding to the promoter region Plpp1 and thereby suppressed Plpp1 expression. PD-1 blockade increased Plpp1 expression and restored CD8+ T cell antitumor function but did not rescue dysfunction of Plpp1-/- CD8+ T cells. Thus, PD-1 signaling regulates phospholipid metabolism in CD8+ T cells, with therapeutic implications for immunotherapy.
    Keywords:  CD8(+) T cell; PD-1 signaling; PLPP1; anti-PD-1 therapy; antitumor immunity; ferroptosis; lipid peroxidation; phospholipid metabolism; tumor microenvironment; unsaturated fatty acid
    DOI:  https://doi.org/10.1016/j.immuni.2024.08.003
  7. Oncoimmunology. 2024 ;13(1): 2392897
    CD4+ tumor-infiltrating lymphocytes secreting T cell-engagers induce regression of autologous patient-derived non-small cell lung cancer xenografts.
    Anaïs Jiménez-Reinoso, Magdalena Molero-Abraham, Cristina Cirauqui, Belén Blanco, Eva M Garrido-Martin, Daniel Nehme-Álvarez, Carmen Domínguez-Alonso, Ángel Ramírez-Fernández, Laura Díez-Alonso, Ángel Nuñez-Buiza, África González-Murillo, Raquel Tobes, Eduardo Pareja, Manuel Ramírez-Orellana, José Luis Rodriguez-Peralto, Irene Ferrer, Jon Zugazagoitia, Luis Paz-Ares, Luis Álvarez-Vallina.
      Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown remarkable results in melanoma, but only modest clinical benefits in other cancers, even after TIL have been genetically modified to improve their tumor homing, cytotoxic potential or overcome cell exhaustion. The required ex vivo TIL expansion process may induce changes in the T cell clonal composition, which could likely compromise the tumor reactivity of TIL preparations and ultimately the success of TIL therapy. A promising approach based on the production of bispecific T cell-engagers (TCE) by engineered T cells (STAb-T therapy) improves the efficacy of current T cell redirection strategies against tumor-associated antigens in hematological tumors. We studied the TCRβ repertoire in non-small cell lung cancer (NSCLC) tumors and in ex vivo expanded TIL from two unrelated patients. We generated TIL secreting anti-epidermal growth factor receptor (EGFR) × anti-CD3 TCE (TILSTAb) and tested their antitumor efficacy in vitro and in vivo using a NSCLC patient-derived xenograft (PDX) model in which tumor fragments and TIL from the same patient were transplanted into hIL-2 NOG mice. We confirmed that the standard TIL expansion protocol promotes the loss of tumor-dominant T cell clones and the overgrowth of virus-reactive TCR clonotypes that were marginally detectable in primary tumors. We demonstrated the antitumor activity of TILSTAb both in vitro and in vivo when administered intratumorally and systemically in an autologous immune-humanized PDX EGFR+ NSCLC mouse model, where tumor regression was mediated by TCE-redirected CD4+ TIL bearing non-tumor dominant clonotypes.
    Keywords:  Adoptive cell therapy; bispecific T cell-engagers; cytotoxic CD4+ TIL; solid tumors; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1080/2162402X.2024.2392897
  8. Blood Adv. 2024 Aug 30. pii: bloodadvances.2024012599. [Epub ahead of print]
    Local Radiation Enhances Systemic CAR T Cell Efficacy by Augmenting Antigen Cross-Presentation and T-cell Infiltration.
    Nektarios Kostopoulos, Francesca Costabile, Elisavet Krimitza, Silvia Beghi, Denisa Goia, Renzo Perales-Linares, George Thyfronitis, Michael J LaRiviere, Elise A Chong, Stephen J Schuster, Amit Maity, Constantinos Koumenis, John P Plastaras, Andrea Facciabene.
      Chimeric antigen receptor (CAR) T cell therapy targeting CD19 (CART-19) represents a significant advance in the treatment of patients with relapsed or refractory CD19-positive B-cell lymphomas. However, a significant portion of patients either relapse or fail to respond. Moreover, many patients have symptomatic disease, requiring bridging radiation therapy (RT) during the period of CAR-T cells manufacturing. To investigate the impact of 1-2 fractions of low-dose RT on CART-19 treatment response, we developed a mouse model using A20 lymphoma cells for CART-19 therapy. We found that low dose fractionated RT had a positive effect on generating abscopal systemic antitumor responses beyond the irradiated site. The combination of RT with CART-19 therapy resulted in additive effects on tumor growth in irradiated masses. Notably, a significant additional increase in antitumor effect was observed in non-irradiated tumors. Mechanistically, our results validate activation of the cGAS/STING pathway, tumor-associated antigen (TAA) cross-priming, and elicitation of epitope spreading. Collectively, our findings suggest that RT may serve as an optimal priming and bridging modality for CAR-T cell therapy overcoming treatment resistance and improving clinical outcomes in patients with CD19-positive hematologic malignancies.
    DOI:  https://doi.org/10.1182/bloodadvances.2024012599
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