The Functional Immune Cell Modulation Division is engaged in the development of T cell-based immunotherapies for the treatment of patients with advanced tumors. Our multifaceted approach is organized into three distinct but interconnected programs, each contributing to the overarching goal of enhancing the therapeutic efficacy of T cells against cancer.

01 | Basic Discovery Program

In the Basic Discovery Program, we delve deep into the molecular mechanisms that govern T-cell differentiation and stemness. Our mission is to uncover the molecular networks orchestrating these vital processes and develop innovative strategies for modulating them within antitumor T cells. This includes manipulation at various levels, from transcription factors (Gattinoni L. et al, Nature Med, 2009; Ji Y. et al, Nature Immunol, 2013; Gautam S. et al, Nature Immunol, 2019), and epigenetic regulators (Ji Y. et al, Nature Commun, 2019) to microRNAs (Ji Y. et al, Proc Natl Acad Sci USA, 2015), and metabolic pathways (Sukumar M. et al, J Clin Invest 2013, Hermans D. et al, Proc Natl Acad Sci USA, 2020).

More recently, our division has embarked on pioneering endeavors to reprogram T-cell function by leveraging intercellular communication mechanisms such as exosome-mediated delivery of microRNAs and nanotube-mediated organelle trafficking (Baldwin J.G. et al., Cell, 2024). These innovative approaches hold the promise of further enhancing T-cell therapeutic potential.

02 | Preclinical Development Program

Building upon the insights gained from our Basis Discovery Program, the Preclinical Development Program serves as a bridge between benchside discoveries and bedside applications. We translate our reprogramming strategies into practical interventions by implementing them in human T cells. Through rigorous evaluation in humanized xenograft models, we gain crucial insights into the in vivo effectiveness of these approaches (Gattinoni L. et al, Nature Med, 2011).

03 | Clinical Cell Manufacturing Program

The Clinical Cell Manufacturing Program is dedicated to taking our groundbreaking discoveries to the next level—direct application in early phase-I/II clinical trials. To achieve this, we develop Good Manufacturing Practice (GMP)-grade cell-processing protocols and standard operating procedures. Our aim is to ensure the safety and efficacy of these novel therapies, laying the foundation for their use in clinical settings (Sabatino M. et al, Blood, 2016).

One major focus for our investigation is the development of immunotherapies based on the adoptive transfer of T memory stem cells (Tscm). A clinical-grade process for the manufacturing of CAR-modified Tscm has been successfully developed, and this innovative platform will serve as a launch pad for the next wave of adoptive Tscm-based immunotherapies (Gattinoni L. et al, Nature Med, 2017).

Visit the complete list of our Research Division’s publications on Google Scholar:

https://scholar.google.com/citations?user=qL6ESpUAAAAJ&hl=en

Here is a selection of the most important publications from the last few years:

Baldwin JG, Heuser-Loy C, Saha T, Schelker RC, Slavkovic-Lukic D, Strieder N, Hernandez-Lopez I, Rana N, Barden M, Mastrogiovanni F, Martín-Santos A, Raimondi A, Brohawn P, Higgs BW, Gebhard C, Kapoor V, Telford WG, Gautam S, Xydia M, Beckhove P, Frischholz S, Schober K, Kontarakis Z, Corn JE, Iannacone M, Inverso D, Rehli M, Fioravanti J, Sengupta S, Gattinoni L. Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy. Cell 2024 Nov 14;187(23):6614-6630.e21. doi: 10.1016/j.cell.2024.08.029.PMID: 39276774

Schelker RC, Fioravanti J, Mastrogiovanni F, Baldwin JG, Rana N, Li P, Chen P, Vadász T, Spolski R, Heuser-Loy C, Slavkovic-Lukic D, Noronha P, Damiano G, Raccosta L, Maggioni D, Pullugula S, Lin JX, Oh J, Grandinetti P, Lecce M, Hesse L, Kocks E, Martín-Santos A, Gebhard C, Telford WG, Ji Y, Restifo NP, Russo V, Rehli M, Herr W, Leonard WJ, Gattinoni L. LIM-domain-only 4 (LMO4) enhances CD8+ T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling. Signal Transduct Target Ther. 2024 Aug 9;9(1):199. doi: 10.1038/s41392-024-01915-z. PMID: 39117617

Gautam S, Fioravanti J, Zhu W, Le Gall JB, Brohawn P, Lacey NE, Hu J, Hocker JD, Hawk NV, Kapoor V, Telford WG, Gurusamy D, Yu Z, Bhandoola A, Xue HH, Roychoudhuri R, Higgs BW, Restifo NP, Bender TP, Ji Y, Gattinoni L. The transcription factor c-Myb regulates CD8+ T cell stemness and antitumor immunity. Nat Immunol. 2019 Mar;20(3):337-349. doi: 10.1038/s41590-018-0311-z. PMID: 30778251

Ji Y, Fioravanti J, Zhu W, Wang H, Wu T, Hu J, Lacey NE, Gautam S, Le Gall J, Yang X, Hocker JD, Escobar TM, He S, Dell’Orso S, Hawk NV, Kapoor V, Telford WG, Di Croce L, Muljo SA, Zhang Y, Sartorelli V, Gattinoni L. miR-155 harnesses Phf19 to potentiate cancer immunotherapy through epigenetic reprogramming of T cell fate. Nat Commun. 2019 May 14;10(1):2157. doi: 10.1038/s41467-019-09882-8. PMID: 31089138

Sabatino M, Hu J, Sommariva M, Gautam S, Fellowes V, Hocker JD, Dougherty S, Qin H, Klebanoff CA, Fry TJ, Gress RE, Kochenderfer JN, Stroncek DF, Ji Y, Gattinoni L. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. Blood. 2016 Jul 28;128(4):519-28. doi: 10.1182/blood-2015-11-683847. PMID: 27226436

Ji Y, Wrzesinski C, Yu Z, Hu J, Gautam S, Hawk NV, Telford WG, Palmer DC, Franco Z, Sukumar M, Clever D, Roychoudhuri R, Klebanoff CA, Surh CD, Waldmann, TA, Restifo, NP, Gattinoni L. miR-155 augments CD8+ T cell anti-tumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γc cytokines. Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):476-81. doi: 10.1073/pnas.1422916112. PMID: 25548153

Sukumar M, Liu J, Ji Y, Subramanian M, Crompton JG, Yu Z, Roychoudhuri R, Palmer DC, Muranski P, Karoly ED, Mohney RP, Klebanoff CA, Lal A, Finkel T, Restifo NP, Gattinoni L. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and anti-tumor function. J Clin Invest. 2013 Sep 16. doi: 10.1172/JCI69589. PMID: 24091329

Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, Almeida JR, Gostick, E, Yu Z, Carpenito C, Wang E, Douek DC, Price DA, June CH, Marincola FM, Roederer M, Restifo NP. A human T cell memory subset with stem cell-like properties. Nat Med. 2011 Sep 18;17(10):1290-7. doi: 10.1038/nm.2446. PMID: 21926977

Ji Y, Pos Z, Rao M, Klebanoff CA, Yu Z, Sukumar M, Reger RN, Palmer DC, Borman ZA, Muranski P, Wang E, Schrump DS, Marincola FM, Restifo NP, Gattinoni L. Repression of the DNA-binding inhibitor Id3 by Blimp1 limits the formation of memory CD8+ T cells. Nat Immunol. 2011 Nov 6;12(12):1230-7. doi: 10.1038/ni.2153. PMID: 22057288

Gattinoni L, Zhong XS, Palmer DC, Ji Y, Hinrichs CS, Yu Z, Wrzesinski C, Boni A, Cassard L, Church L, Paulos CM, Muranski P, Restifo NP. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med. 2009 Jul;15(7):808-13. doi: 10.1038/nm.1982. PMID: 19525962

We are dedicated to developing innovative cell-therapy initiatives for the treatment of patients with advanced cancer. Late-phase development projects include:

Collaboration with Miltenyi Biotec

Together, we are developing a cGMP-compliant, semi-automated manufacturing platform for the generation of CD22/CD19-bispecific CD8⁺ Tscm cells. The cellular product developed will be tested in patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma.

Collaboration with Poseida Therapeutics

Together, we are developing a manufacturing platform for the generation of NY-ESO-1-TCR redirected Tscm cells, functionally empowered through the overexpression of human miR-155 SNP rs377265631. The cellular product developed will be tested in patients with relapsed or refractory sarcoma.

We participate in several national and international research consortia:

EIC-Pathfinder T-FITNESS: Fine-Tuning Networks of Exhaustion by Synthetic Sensors

This EU consortium aims to generate antitumor T cells which are refractory to terminal differentiation and dysfunction. This ambitious goal will be pursued through the development of innovative microRNA-based synthetic logic circuits capable of rewiring the transcriptional programs driving T-cell exhaustion. The leadership and coordination of this project are centered at the LIT, where our primary focus lies in comprehensively characterizing the phenotype, function, and metabolic profiles of T cells that have undergone reprogramming using T-FITNESS technology.

https://www.t-fitness-horizon.eu/

EIC Pathfinder INCITE: Immune Niches for Cancer Immunotherapy Enhancement

This EU consortium seeks to develop a 3D-printed immune niche microenvironment for the generation and expansion of tumor-specific stem cell memory T cells. Within this consortium, we are responsible for functionally evaluating human CAR T cells generated within INCITE artificial immune niches and comparing them with those manufactured with the current technology.

https://incite.eu.com/

CRC/ TR221 – GvHGvL

The focus of this national consortium is to improve the safety and efficacy of allogeneic stem cell transplantation by developing innovative strategies to modulate graft-versus-host and graft-versus-leukemia immune responses. Our role in this Collaborative Research Center is to investigate whether donor-derived CAR-modified CD8⁺ T memory stem cells provide a safer and more effective platform to treat human B-cell malignancies which have relapsed after allogeneic stem cell transplantation.

https://www.gvhgvl.de/

We would like to thank the funding agencies who support our work:

2025-2026: National Strategy for Gene and Cell Therapies project funding program (SPARK-GCT)
Clinical-grade manufacturing of NY-ESO-1 TCR-modified stem-like T cells overexpressing the pre-miR-155 SNP, rs377265631.

2024-2030: German Cancer Aid (DKH), Cancer Therapy Studies
A phase I safety, dose-finding, and feasibility trial of LIT-TSCM-CART-CD22/19 in patients with relapsed or refractory aggressive B cell Non-Hodgkin lymphoma.

2022–2027: German Research Foundation (DFG), Reinhart Koselleck Project
Reprogramming CD8⁺ T-cell metabolism and fate by MSC mitochondrial transfer.

2022–2026: EIC Pathfinder Challenges 2021
Fine-tuning T-cell networks in exhaustion using synthetic sensors.

2021–2025: German Research Foundation (DFG), CRC/ TR221, Project A07
Enhancing graft-versus-leukemia responses by donor-derived CAR-modified CD8+ T memory stem cells.

2021–2025: EIC Pathfinder
Immune niches for cancer immunotherapy enhancement.

Prof. Luca Gattinoni

Head of Research Division | Functional Immune Cell Modulation

Tel: +49 941 944–38131
Email: luca.gattinoni@lit.eu

Katrin Zehenter

Team Assistant

Tel: +49 941 944–38132
Email: katrin.zehenter@ukr.de

Research team

Prof. Luca Gattinoni

Head of Research Division | Functional Immune Cell Modulation

Dr. Roland Schelker

Postdoctoral Scientist

Dr. Dragana Slavkovic-Lukic

Senior Scientist

Dr. Christoph Heuser-Loy

Senior Scientist

Dr. Jeremy Baldwin

Postdoctoral Scientist

Dr. Esen Sayin

Postdoctoral Scientist

Dr. Maka Malania

Project Manager

Nisha Rana

Bioinformatician

Gabriele Inchingolo

PhD Student

Timea Vadász

PhD Student

Dr. Caio Silveira

Postdoctoral Scientist

Fabio Mastrogiovanni

Research Technician

Pedro Noronha

Research Technician

Azucena Martin

Research Technician

Dr. Asia Majidi

Postdoctoral Scientist

Lab Life

There is life outside the laboratory: The Leibniz Institute places great value on our scientists developing the team spirit both in and out of work. Here are the photos to prove it!