bims-adocet 2024-09-29 papers

bims-adocet

Biomed News

on Adoptive cell therapy

Issue of 2024–09–29
twelve papers selected by
Shani Kassia Lyskov, Tel Aviv University

Cytokine-mediated CAR T therapy resistance in AML.
Single-cell CAR T atlas reveals type 2 function in 8-year leukaemia remission.
Microbial metabolite-guided CAR T cell engineering enhances anti-tumor immunity via epigenetic-metabolic crosstalk.
Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy.
Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy.
Preclinical Evaluation of AZD6422, an Armored Chimeric Antigen Receptor T Cell Targeting CLDN18.2 in Gastric, Pancreatic, and Esophageal Cancer.
Acarbose enhances the efficacy of immunotherapy against solid tumours by modulating the gut microbiota.
The type 2 cytokine Fc-IL-4 revitalizes exhausted CD8+ T cells against cancer.
Localized ablative immunotherapy enhances antitumor immunity by modulating the transcriptome of tumor-infiltrating Gamma delta T cells.
A PD-1-targeted, receptor-masked IL-2 immunocytokine that engages IL-2Rα strengthens T cell-mediated anti-tumor therapies.
Histone marks identify novel transcription factors that parse CAR-T subset-of-origin, clinical potential and expansion.
Engineered allogeneic T cells decoupling T-cell-receptor and CD3 signalling enhance the antitumour activity of bispecific antibodies.

Nat Med. 2024 Sep 27.

Cytokine-mediated CAR T therapy resistance in AML.

Anand S Bhagwat, Leonel Torres, Olga Shestova, Maksim Shestov, Patrick W Mellors, Han R Fisher, Saamia N Farooki, Benjamin F Frost, Michael R Loken, Avery L Gaymon, Diane Frazee, Walter Rogal, Noelle Frey, Elizabeth O Hexner, Selina M Luger, Alison W Loren, Mary Ellen Martin, Shannon R McCurdy, Alexander E Perl, Edward A Stadtmauer, Jennifer L Brogdon, Joseph A Fraietta, Wei-Ting Hwang, Don L Siegel, Gabriela Plesa, Richard Aplenc, David L Porter, Carl H June, Saar I Gill.

Acute myeloid leukemia (AML) is a rapidly progressive malignancy without effective therapies for refractory disease. So far, chimeric antigen receptor (CAR) T cell therapy in AML has not recapitulated the efficacy seen in B cell malignancies. Here we report a pilot study of autologous anti-CD123 CAR T cells in 12 adults with relapsed or refractory AML. CAR T cells targeting CD123+ cells were successfully manufactured in 90.4% of runs. Cytokine release syndrome was observed in 10 of 12 infused individuals (83.3%, 90% confidence interval 0.5-0.97). Three individuals achieved clinical response (25%, 90% confidence interval 0.07-0.53). We found that myeloid-supporting cytokines are secreted during cell therapy and support AML blast survival via kinase signaling, leading to CAR T cell exhaustion. The prosurvival effect of therapy-induced cytokines presents a unique resistance mechanism in AML that is distinct from any observed in B cell malignancies. Our findings suggest that autologous CART manufacturing is feasible in AML, but treatment is associated with high rates of cytokine release syndrome and relatively poor clinical efficacy. Combining CAR T cell therapies with cytokine signaling inhibitors could enhance immunotherapy efficacy in AML and achieve improved outcomes (ClinicalTrials.gov identifier: NCT03766126 ).

DOI: https://doi.org/10.1038/s41591-024-03271-5
Nature. 2024 Sep 25.

Single-cell CAR T atlas reveals type 2 function in 8-year leukaemia remission.

Zhiliang Bai, Bing Feng, Susan E McClory, Beatriz Coutinho de Oliveira, Caroline Diorio, Céline Gregoire, Bo Tao, Luojia Yang, Ziran Zhao, Lei Peng, Giacomo Sferruzza, Liqun Zhou, Xiaolei Zhou, Jessica Kerr, Alev Baysoy, Graham Su, Mingyu Yang, Pablo G Camara, Sidi Chen, Li Tang, Carl H June, J Joseph Melenhorst, Stephan A Grupp, Rong Fan.

Despite a high response rate in chimeric antigen receptor (CAR) T cell therapy for acute lymphocytic leukaemia (ALL)1-3, approximately 50% of patients relapse within the first year4-6, representing an urgent question to address in the next stage of cellular immunotherapy. Here, to investigate the molecular determinants of ultralong CAR T cell persistence, we obtained a single-cell multi-omics atlas from 695,819 pre-infusion CAR T cells at the basal level or after CAR-specific stimulation from 82 paediatric patients with ALL enrolled in the first two CAR T ALL clinical trials and 6 healthy donors. We identified that elevated type 2 functionality in CAR T infusion products is significantly associated with patients maintaining a median B cell aplasia duration of 8.4 years. Analysis of ligand-receptor interactions revealed that type 2 cells regulate a dysfunctional subset to maintain whole-population homeostasis, and the addition of IL-4 during antigen-specific activation alleviates CAR T cell dysfunction while enhancing fitness at both transcriptomic and epigenomic levels. Serial proteomic profiling of sera after treatment revealed a higher level of circulating type 2 cytokines in 5-year or 8-year relapse-free responders. In a leukaemic mouse model, type 2high CAR T cell products demonstrated superior expansion and antitumour activity, particularly after leukaemia rechallenge. Restoring antitumour efficacy in type 2low CAR T cells was attainable by enhancing their type 2 functionality, either through incorporating IL-4 into the manufacturing process or by priming manufactured CAR T products with IL-4 before infusion. Our findings provide insights into the mediators of durable CAR T therapy response and suggest potential therapeutic strategies to sustain long-term remission by boosting type 2 functionality in CAR T cells.

DOI: https://doi.org/10.1038/s41586-024-07762-w
bioRxiv. 2024 Sep 13. pii: 2024.08.19.608538. [Epub ahead of print]

Microbial metabolite-guided CAR T cell engineering enhances anti-tumor immunity via epigenetic-metabolic crosstalk.

Sarah Staudt, Fabian Nikolka, Markus Perl, Julia Franz, Noemie Leblay, Xiaoli-Kat Yuan, Linda Warmuth, Matthias A Fantes, Aiste Skorpskaite, Teng Fei, Maria Bromberg, Patxi San Martin-Uriz, Juan Roberto Rodriguez-Madoz, Kai Ziegler-Martin, Nazdar Adil-Gholam, Pascal Benz, Phuc Tran Huu, Christoph Stein-Thoeringer, Michael Schmitt, Karin Kleigrewe, Fabian Freitag, Zeno Riester, Justus Weber, Kira Mangold, Hermann Einsele, Felipe Prosper, Wilfried Ellmeier, Dirk Busch, Alexander Visekruna, John Slingerland, Roni Shouval, Karsten Hiller, Marcel van den Brink, Patrick Pausch, Paola Neri, Michael Hudecek, Hendrik Poeck, Maik Luu.

Emerging data have highlighted a correlation between microbiome composition and cancer immunotherapy outcome. While commensal bacteria and their metabolites are known to modulate the host environment, contradictory effects and a lack of mechanistic understanding impede the translation of microbiome-based therapies into the clinic. In this study, we demonstrate that abundance of the commensal metabolite pentanoate is predictive for survival of chimeric antigen receptor (CAR) T cell patients in two independent cohorts. Its implementation in the CAR T cell manufacturing workflow overcomes solid tumor microenvironments in immunocompetent cancer models by hijacking the epigenetic-metabolic crosstalk, reducing exhaustion and promoting naive-like differentiation. While synergy of clinically relevant drugs mimicked the phenotype of pentanoate-engineered CAR T cells in vitro, in vivo challenge showed inferior tumor control. Metabolic tracing of 13C-pentanoate revealed citrate generation in the TCA cycle via the acetyl- and succinyl-CoA entry points as a unique feature of the C5 aliphatic chain. Inhibition of the ATP-citrate lyase, which links metabolic output and histone acetylation, led to accumulation of pentanoate-derived citrate from the succinyl-CoA route and decreased functionality of SCFA-engineered CAR T cells. Our data demonstrate that microbial metabolites are incorporated as epigenetic imprints and implementation into CAR T cell production might serve as embodiment of the microbiome-host axis benefits for clinical applications.

DOI: https://doi.org/10.1101/2024.08.19.608538
Nat Immunol. 2024 Oct;25(10): 1884-1899

Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy.

Geoffrey J Markowitz, Yi Ban, Diamile A Tavarez, Liron Yoffe, Enrique Podaza, Yongfeng He, Mitchell T Martin, Michael J P Crowley, Tito A Sandoval, Dingcheng Gao, M Laura Martin, Olivier Elemento, Juan R Cubillos-Ruiz, Timothy E McGraw, Nasser K Altorki, Vivek Mittal.

TCF1high progenitor CD8+ T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-13C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells toward a TCF1high population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8+ T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state promoting immunotherapy efficacy.

DOI: https://doi.org/10.1038/s41590-024-01963-1
Nat Commun. 2024 Sep 27. 15(1): 8354

Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy.

Avishai Maliah, Nadine Santana-Magal, Shivang Parikh, Sagi Gordon, Keren Reshef, Yuval Sade, Aseel Khateeb, Alon Richter, Amit Gutwillig, Roma Parikh, Tamar Golan, Matan Krissi, Manho Na, Gal Binshtok, Paulee Manich, Nadav Elkoshi, Sharon Grisaru-Tal, Valentina Zemser-Werner, Ronen Brenner, Hananya Vaknine, Eran Nizri, Lilach Moyal, Iris Amitay-Laish, Luiza Rosemberg, Ariel Munitz, Noga Kronfeld-Schor, Eric Shifrut, Oren Kobiler, Asaf Madi, Tamar Geiger, Yaron Carmi, Carmit Levy.

T cell inhibitory mechanisms prevent autoimmune reactions, while cancer immunotherapy aims to remove these inhibitory signals. Chronic ultraviolet (UV) exposure attenuates autoimmunity through promotion of poorly understood immune-suppressive mechanisms. Here we show that mice with subcutaneous melanoma are not responsive to anti-PD1 immunotherapy following chronic UV irradiation, given prior to tumor injection, due to the suppression of T cell killing ability in skin-draining lymph nodes. Using mass cytometry and single-cell RNA-sequencing analyzes, we discover that skin-specific, UV-induced suppression of T-cells killing activity is mediated by upregulation of a Ly6ahigh T-cell subpopulation. Independently of the UV effect, Ly6ahigh T cells are induced by chronic type-1 interferon in the tumor microenvironment. Treatment with an anti-Ly6a antibody enhances the anti-tumoral cytotoxic activity of T cells and reprograms their mitochondrial metabolism via the Erk/cMyc axis. Treatment with an anti-Ly6a antibody inhibits tumor growth in mice resistant to anti-PD1 therapy. Applying our findings in humans could lead to an immunotherapy treatment for patients with resistance to existing treatments.

DOI: https://doi.org/10.1038/s41467-024-52079-x
Clin Cancer Res. 2024 Sep 25.

Preclinical Evaluation of AZD6422, an Armored Chimeric Antigen Receptor T Cell Targeting CLDN18.2 in Gastric, Pancreatic, and Esophageal Cancer.

Allison M Barrett, Zachary T Britton, Rosa A Carrasco, Shannon Breen, Maria A S Broggi, Amy Hatke, Benjamin Clark, Chunning Yang, Sandrina Phipps, Lorenzo Ortiz, Brianna Janocha, Peter Zanvit, Nicolas A Giraldo, Philip L Martin, Jean-Martin Lapointe, Nathalie Harder, Georgina H Cornish, Bala N N R Attili, Yariv Mazor, Melissa Damschroder, Mark Cobbold, Gordon Moody, Emily E Bosco.

PURPOSE: CLDN18.2 is a surface membrane protein crucial for maintaining tight junctions in gastric mucosal cells and is highly expressed in gastric, esophageal, and pancreatic cancers. Thus, CLDN18.2 is suited for exploration as a clinical target for chimeric antigen receptor T-cell (CAR-T) therapy in these indications. Although CAR-T therapies show promise, a challenge faced in their development for solid tumors is the immunosuppressive tumor microenvironment, often characterized by the presence of immune and stromal cells secreting high levels of transforming growth factor beta (TGF-β). Addition of TGF-β armoring can potentially expand CAR-T activity in solid tumors. We report on the preclinical development of a CLDN18.2-targeting CAR-T showing effectiveness in CLDN18.2-positive gastric, esophageal, and pancreatic tumor models.
EXPERIMENTAL DESIGN: The lead lentivirus product contains a unique single-chain variable fragment, CD28 and CD3z costimulatory and signaling domains, and dominant negative TGF-β receptor armoring, enhancing targeting and safety and counteracting suppression. We developed a shortened cell manufacturing process to enhance the potency of the final product, AZD6422.
RESULTS: AZD6422 exhibited significant antitumor activity and tolerability in multiple patient-derived tumor xenograft models with various CLDN18.2 and TGF-β levels, as determined by immunohistochemistry. Efficacy of armored CAR-Ts in tumor models with elevated TGF-β was increased in vitro and in vivo. In vitro restimulation assays established greater persistence and cytolytic function of AZD6422 compared with a traditionally manufactured CAR-T.
CONCLUSIONS: AZD6422 was safe and efficacious in patient-derived, CLDN18.2-positive murine models of gastrointestinal cancers. Our data support further clinical development of AZD6422 for patients with these cancers.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-1853
Nat Metab. 2024 Sep 25.

Acarbose enhances the efficacy of immunotherapy against solid tumours by modulating the gut microbiota.

Shi-Long Zhang, Xin Wang, Qing-Qing Cai, Chen Chen, Zheng-Yan Zhang, Ya-Yun Xu, Meng-Xuan Yang, Qing-An Jia, Yan Wang, Zhi-Ming Wang.

The crucial role of gut microbiota in shaping immunotherapy outcomes has prompted investigations into potential modulators. Here we show that oral administration of acarbose significantly increases the anti-tumour response to anti-PD-1 therapy in female tumour-bearing mice. Acarbose modulates the gut microbiota composition and tryptophan metabolism, thereby contributing to changes in chemokine expression and increased T cell infiltration within tumours. We identify CD8+ T cells as pivotal components determining the efficacy of the combined therapy. Further experiments reveal that acarbose promotes CD8+ T cell recruitment through the CXCL10-CXCR3 pathway. Faecal microbiota transplantation and gut microbiota depletion assays indicate that the effects of acarbose are dependent on the gut microbiota. Specifically, acarbose enhances the efficacy of anti-PD-1 therapy via the tryptophan catabolite indoleacetate, which promotes CXCL10 expression and thus facilitates CD8+ T cell recruitment, sensitizing tumours to anti-PD-1 therapy. The bacterial species Bifidobacterium infantis, which is enriched by acarbose, also improves response to anti-PD-1 therapy. Together, our study endorses the potential combination of acarbose and anti-PD-1 for cancer immunotherapy.

DOI: https://doi.org/10.1038/s42255-024-01137-1
Nature. 2024 Sep 25.

The type 2 cytokine Fc-IL-4 revitalizes exhausted CD8+ T cells against cancer.

Bing Feng, Zhiliang Bai, Xiaolei Zhou, Yang Zhao, Yu-Qing Xie, Xinyi Huang, Yang Liu, Tom Enbar, Rongrong Li, Yi Wang, Min Gao, Lucia Bonati, Mei-Wen Peng, Weilin Li, Bo Tao, Mélanie Charmoy, Werner Held, J Joseph Melenhorst, Rong Fan, Yugang Guo, Li Tang.

Current cancer immunotherapy predominately focuses on eliciting type 1 immune responses fighting cancer; however, long-term complete remission remains uncommon1,2. A pivotal question arises as to whether type 2 immunity can be orchestrated alongside type 1-centric immunotherapy to achieve enduring response against cancer3,4. Here we show that an interleukin-4 fusion protein (Fc-IL-4), a typical type 2 cytokine, directly acts on CD8+ T cells and enriches functional terminally exhausted CD8+ T (CD8+ TTE) cells in the tumour. Consequently, Fc-IL-4 enhances antitumour efficacy of type 1 immunity-centric adoptive T cell transfer or immune checkpoint blockade therapies and induces durable remission across several syngeneic and xenograft tumour models. Mechanistically, we discovered that Fc-IL-4 signals through both signal transducer and activator of transcription 6 (STAT6) and mammalian target of rapamycin (mTOR) pathways, augmenting the glycolytic metabolism and the nicotinamide adenine dinucleotide (NAD) concentration of CD8+ TTE cells in a lactate dehydrogenase A-dependent manner. The metabolic modulation mediated by Fc-IL-4 is indispensable for reinvigorating intratumoural CD8+ TTE cells. These findings underscore Fc-IL-4 as a potent type 2 cytokine-based immunotherapy that synergizes effectively with type 1 immunity to elicit long-lasting responses against cancer. Our study not only sheds light on the synergy between these two types of immune responses, but also unveils an innovative strategy for advancing next-generation cancer immunotherapy by integrating type 2 immune factors.

DOI: https://doi.org/10.1038/s41586-024-07962-4
Cancer Lett. 2024 Sep 20. pii: S0304-3835(24)00662-1. [Epub ahead of print]604 217267

Localized ablative immunotherapy enhances antitumor immunity by modulating the transcriptome of tumor-infiltrating Gamma delta T cells.

Kaili Liu, Ashley R Hoover, Lin Wang, Yuanhong Sun, Trisha I Valerio, Coline Furrer, Jacob Adams, Jingxuan Yang, Min Li, Wei R Chen.

  Gamma delta T cells (γδT cells) play crucial roles in the immune response against tumors, yet their functional dynamics under different cancer therapies remain poorly understood. Laser Ablative Immunotherapy (LAIT) is a novel cancer treatment modality combining local photothermal therapy (PTT) and intratumoral injection of an immunostimulant, N-dihydrogalactochitosan (glycated chitosan, GC). LAIT has been shown to induce systemic antitumor immune responses in pre-clinical studies and clinical trials, eradicating both treated local tumors and untreated distant metastases. In this study, we used LAIT to treat breast tumors in a mouse model and investigated the effects of LAIT on tumor-infiltrating γδT cells using single-cell RNA sequencing (scRNAseq). We characterized the γδT cells from tumors in control, PTT, GC, and LAIT (PTT + GC) groups, by identifying six distinct subtypes: activated, cytotoxic, cycling cytotoxic, IFN-enriched, antigen-presenting, and IL17-producing γδT cells. Differential gene expression analysis revealed that LAIT significantly upregulated genes associated with T cell activation, leukocyte adhesion, and interferon signaling in treated tumor tissues while downregulating genes involved in protein folding and stress responses. LAIT also uniquely increased the proportion of IL17-producing γδT cells, which correlated with prolonged survival in breast cancer patients, as analyzed using TCGA data. Furthermore, the transcriptomic profiles of γδT cells in LAIT-treated tumors closely resembled those in immune checkpoint inhibitor (ICI)-treated patients, suggesting potential synergistic effects. Our findings indicate that LAIT modulates the γδT cell transcriptome, enhancing their antitumor capabilities and providing a basis for combining LAIT with ICI therapy to improve cancer treatment outcomes.

Keywords:  Breast cancer; Localized ablative immunotherapy; N-dihydrogalactochitosan; Single-cell RNA sequencing; γδT cell activation

DOI:  https://doi.org/10.1016/j.canlet.2024.217267
Cell Rep Med. 2024 Sep 17. pii: S2666-3791(24)00477-4. [Epub ahead of print] 101747

A PD-1-targeted, receptor-masked IL-2 immunocytokine that engages IL-2Rα strengthens T cell-mediated anti-tumor therapies.

Jiaxi Wu, Nicolin Bloch, Aaron Y Chang, Ramandeep Bhavsar, Qingqing Wang, Alison Crawford, David J DiLillo, Kristin Vazzana, Katja Mohrs, Drew Dudgeon, Supriya Patel, Hassan Ahmed, Vidur Garg, Michael Amatulli, Olivia Q Antao, Yuetian Yan, Shunhai Wang, Willy Ramos, Pamela Krueger, Christina Adler, Min Ni, Yi Wei, Chunguang Guo, Lynn Macdonald, Tammy Huang, Erica Ullman, Aynur Hermann, George D Yancopoulos, Andrew J Murphy, Samuel Davis, William C Olson, John C Lin, Eric Smith, Tong Zhang.

The clinical use of interleukin-2 (IL-2) for cancer immunotherapy is limited by severe toxicity. Emerging IL-2 therapies with reduced IL-2 receptor alpha (IL-2Rα) binding aim to mitigate toxicity and regulatory T cell (Treg) expansion but have had limited clinical success. Here, we show that IL-2Rα engagement is critical for the anti-tumor activity of systemic IL-2 therapy. A "non-α" IL-2 mutein induces systemic expansion of CD8+ T cells and natural killer (NK) cells over Tregs but exhibits limited anti-tumor efficacy. We develop a programmed cell death protein 1 (PD-1)-targeted, receptor-masked IL-2 immunocytokine, PD1-IL2Ra-IL2, which attenuates systemic IL-2 activity while maintaining the capacity to engage IL-2Rα on PD-1+ T cells. Mice treated with PD1-IL2Ra-IL2 show no systemic toxicities observed with unmasked IL-2 treatment yet achieve robust tumor growth control. Furthermore, PD1-IL2Ra-IL2 can be effectively combined with other T cell-mediated immunotherapies to enhance anti-tumor responses. These findings highlight the therapeutic potential of PD1-IL2Ra-IL2 as a targeted, receptor-masked, and "α-maintained" IL-2 therapy for cancer.

DOI: https://doi.org/10.1016/j.xcrm.2024.101747
Nat Commun. 2024 Sep 27. 15(1): 8309

Histone marks identify novel transcription factors that parse CAR-T subset-of-origin, clinical potential and expansion.

S Fiorenza, Y Zheng, J Purushe, T J Bock, J Sarthy, D H Janssens, A S Sheih, E L Kimble, D Kirchmeier, T D Phi, J Gauthier, A V Hirayama, S R Riddell, Q Wu, R Gottardo, D G Maloney, J Y H Yang, S Henikoff, C J Turtle.

Chimeric antigen receptor-modified T cell (CAR-T) immunotherapy has revolutionised blood cancer treatment. Parsing the genetic underpinnings of T cell quality and CAR-T efficacy is challenging. Transcriptomics inform CAR-T state, but the nature of dynamic transcription during activation hinders identification of transiently or minimally expressed genes, such as transcription factors, and over-emphasises effector and metabolism genes. Here we explore whether analyses of transcriptionally repressive and permissive histone methylation marks describe CAR-T cell functional states and therapeutic potential beyond transcriptomic analyses. Histone mark analyses improve identification of differences between naïve, central memory, and effector memory CD8 + T cell subsets of human origin, and CAR-T derived from these subsets. We find important differences between CAR-T manufactured from central memory cells of healthy donors and of patients. By examining CAR-T products from a clinical trial in lymphoma (NCT01865617), we find a novel association between the activity of the transcription factor KLF7 with in vivo CAR-T accumulation in patients and demonstrate that over-expression of KLF7 increases in vitro CAR-T proliferation and IL-2 production. In conclusion, histone marks provide a rich dataset for identification of functionally relevant genes not apparent by transcriptomics.

DOI: https://doi.org/10.1038/s41467-024-52503-2
Nat Biomed Eng. 2024 Sep 25.

Engineered allogeneic T cells decoupling T-cell-receptor and CD3 signalling enhance the antitumour activity of bispecific antibodies.

Edo Kapetanovic, Cédric R Weber, Marine Bruand, Daniel Pöschl, Jakub Kucharczyk, Elisabeth Hirth, Claudius Dietsche, Riyaz Khan, Bastian Wagner, Olivier Belli, Rodrigo Vazquez-Lombardi, Rocío Castellanos-Rueda, Raphael B Di Roberto, Kevin Kalinka, Luca Raess, Kevin Ly, Shivam Rai, Petra S Dittrich, Randall J Platt, Elisa Oricchio, Sai T Reddy.

Bispecific antibodies (biAbs) used in cancer immunotherapies rely on functional autologous T cells, which are often damaged and depleted in patients with haematological malignancies and in other immunocompromised patients. The adoptive transfer of allogeneic T cells from healthy donors can enhance the efficacy of biAbs, but donor T cells binding to host-cell antigens cause an unwanted alloreactive response. Here we show that allogeneic T cells engineered with a T-cell receptor that does not convert antigen binding into cluster of differentiation 3 (CD3) signalling decouples antigen-mediated T-cell activation from T-cell cytotoxicity while preserving the surface expression of the T-cell-receptor-CD3 signalling complex as well as biAb-mediated CD3 signalling and T-cell activation. In mice with CD19+ tumour xenografts, treatment with the engineered human cells in combination with blinatumomab (a clinically approved biAb) led to the recognition and clearance of tumour cells in the absence of detectable alloreactivity. Our findings support the development of immunotherapies combining biAbs and 'off-the-shelf' allogeneic T cells.

DOI: https://doi.org/10.1038/s41551-024-01255-x