A patient-derived T cell lymphoma biorepository uncovers pathogenetic mechanisms and host-related therapeutic vulnerabilities PMID: 40147445

ADC Targets in Oncology

2026-04-10

A patient-derived T cell lymphoma biorepository uncovers pathogenetic mechanisms and host-related therapeutic vulnerabilities

Cell Rep Med. 2025 Apr 15;6(4):102029. doi: 10.1016/j.xcrm.2025.102029.

Danilo Fiore ¹ , Luca Vincenzo Cappelli ² , Liu Zhaoqi ³ , Nikita Kotlov ⁴ , Maria Sorokina ⁴ , Jude Phillip ⁵ , Paul Zumbo ⁶ , Liron Yoffe ⁷ , Paola Ghione ⁸ , Anqi Wang ⁹ , Xueshuai Han ³ , Abigail Taylor ¹⁰ , William Chiu ¹⁰ , Valentina Fragliasso ¹¹ , Fabrizio Tabbo ¹² , Nahuel Zamponi ¹³ , Nicolás Di Siervi ¹³ , Clarisse Kayembe ¹⁰ , Giovanni Medico ¹⁰ , Ruchi P Patel ¹⁴ , Marcello Gaudiano ¹⁰ , Rodolfo Machiorlatti ¹⁵ , Giuseppina Astone ¹⁰ , Maria Teresa Cacciapuoti ¹⁰ , Giorgia Zanetti ¹⁰ , Claudia Pignataro ¹⁶ , Ruiz Arvin Eric ¹⁰ , Sanjay Patel ¹⁰ , Francesca Zammarchi ¹⁷ , Claudio Zanettini ¹⁰ , Lucio Queiroz ¹⁰ , Anastasia Nikitina ⁴ , Olga Kudryashova ⁴ , Anton Karelin ⁴ , Daniil Nikitin ⁴ , Dmitry Tychinin ⁴ , Ekaterina Postovalova ⁴ , Alexander Bagaev ⁴ , Viktor Svekolkin ⁴ , Ekaterina Belova ⁴ , Katerina Tikhonova ⁴ , Sandrine Degryse ⁴ , Chengqi Xu ¹⁸ , Domenico Novero ¹⁹ , Maurilio Ponzoni ²⁰ , Enrico Tiacci ²¹ , Brunangelo Falini ²¹ , Joo Song ²² , Inna Khodos ²³ , Elisa De Stanchina ²³ , Gabriele Macari ²⁴ , Luciana Cafforio ²⁴ , Simone Gardini ²⁴ , Roberto Piva ²⁵ , Enzo Medico ²⁶ , Samuel Y Ng ²⁷ , Allison Moskowitz ⁸ , Zachary Epstein ⁸ , Andrew Intlekofer ⁸ , Dogan Ahmed ²⁸ , Wing C Chan ²² , Peter Martin ²⁹ , Jia Ruan ²⁹ , Francesco Bertoni ³⁰ , Robin Foà ³¹ , Joshua D Brody ³² , David M Weinstock ³³ , Jaspreet Osan ³⁴ , Laura Santambrogio ³⁴ , Oliver Elemento ¹⁸ , Doron Betel ³⁵ , Wayne Tam ³⁶ , Marco Ruella ³⁷ , Leandro Cerchietti ¹³ , Raul Rabadan ⁹ , Steven Horwitz ⁸ , Giorgio Inghirami ³⁸

Affiliations

1. Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; Institute for Experimental Endocrinology and Oncology, "G.Salvatore" IEOS, Consiglio Nazionale delle Ricerche (CNR), 80131 Naples, Italy.
2. Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
3. Program for Mathematical Genomics, Department of Systems Biology, Department of Biomedical Informatics, Columbia University, New York, NY 10027 USA; China National Center for Bioinformation, Beijing, China; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China.
4. BostonGene Corporation, Waltham, MA 02453, USA.
5. Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065 US; Chemical and Biomolecular Engineering, Oncology, Sidney Kimmel Comprehensive Cancer Center, Core Member, Institute for Nanobiotechnology (INBT), Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
6. Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY 10065, USA; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, US.
7. Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA.
8. Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
9. Program for Mathematical Genomics, Department of Systems Biology, Department of Biomedical Informatics, Columbia University, New York, NY 10027 USA.
10. Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA.
11. Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Laboratory of translational research, Azienda USL - IRCCS di Reggio Emilia, 42122 Reggio Emila, Italy.
12. Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; SC Oncologia ASL CN2 Alba Bra Ospedale Michele e Pietro Ferrero, 12060 Verduno, (CN), Italy.
13. Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065 US.
14. Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Perelman Center for Advanced Medicine, SPE 8-112, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA.
15. Department of Pathology, Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy.
16. Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
17. ADC Therapeutics (UK) Limited, London W12 0BZ United Kingdom.
18. Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA.
19. Division of Pathological Anatomy, Quality and Safety of Diagnosis and Treatment, Città della Salute e della Scienza, 10126 Turin, Italy.
20. Pathology Unit, San Raffaele Scientific Institute, Milan, Italy; Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, 20132 Milan, Italy.
21. Institute of Hematology, University of Perugia, Ospedale S. Maria della Misericordia, S. Andrea delle Fratte, 06156 Perugia Italy.
22. Department of Pathology, City of Hope Medical Center, Duarte, CA 91010, US.
23. Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, US.
24. GenomeUp S.r.l., 00144 Rome, RM, Italy.
25. Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; Medical Genetics Unit, Città della Salute e della Scienza University Hospital, 10126 Turin, Italy.
26. Department of Oncology, University of Torino, Candiolo, TO, Italy; Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, TO, Italy.
27. Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; National Cancer Institute, Bethesda, MD 20892, USA.
28. Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
29. Lymphoma Service, Weill Cornell Medical Center, New York, NY 10065, USA.
30. Lymphoma Genomics, Institute of Oncology Research, Faculty of Biomedical Sciences, USI, 6500 Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, EOC,6500 Bellinzona, Switzerland.
31. Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
32. Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, US; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
33. Merck Research Laboratories, Boston, MA 02115, USA.
34. Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA.
35. Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065 US; Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY 10065, USA; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, US.
36. Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Division of Hematopathology, Northwell Health, New York, NY 11740, USA.
37. Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Perelman Center for Advanced Medicine, SPE 8-112, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
38. Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: [email protected].

Abstract

Peripheral T cell lymphomas (PTCLs) comprise heterogeneous malignancies with limited therapeutic options. To uncover targetable vulnerabilities, we generate a collection of PTCL patient-derived tumor xenografts (PDXs) retaining histomorphology and molecular donor-tumor features over serial xenografting. PDX demonstrates remarkable heterogeneity, complex intratumor architecture, and stepwise trajectories mimicking primary evolutions. Combining functional transcriptional stratification and multiparametric imaging, we identify four distinct PTCL microenvironment subtypes with prognostic value. Mechanistically, we discover a subset of PTCLs expressing Epstein-Barr virus-specific T cell receptors and uncover the capacity of cancer-associated fibroblasts of counteracting treatments. PDXs' pre-clinical testing captures individual vulnerabilities, mirrors donor patients' clinical responses, and defines effective patient-tailored treatments. Ultimately, we assess the efficacy of CD5KO- and CD30- Chimeric Antigen Receptor T Cells (CD5KO-CART and CD30_CART, respectively), demonstrating their therapeutic potential and the synergistic role of immune checkpoint inhibitors for PTCL treatment. This repository represents a resource for discovering and validating intrinsic and extrinsic factors and improving the selection of drugs/combinations and immune-based therapies.

Keywords

CAR-T; T cell lymphoma; clonal evolution; drug screenings; microenvironment; patient-derived tumor xenografts; pre-clinical trials; precision medicine; repository; stratification.