CHRONIC LYMPHOCYTIC LEUKEMIA CELLS IMPAIR MITOCHONDRIAL FITNESS IN T CELLS AND IMPEDE CAR T CELL EFFICACY
Author(s): ,
Jaco A. C. Van Bruggen
Affiliations:
Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam,Amsterdam UMC,Amsterdam,Netherlands;Department of Experimental Immunology, Amsterdam Infection & Immunity Institute,Amsterdam UMC,Amsterdam,Netherlands
,
Anne W. J. Martens
Affiliations:
Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam,Amsterdam UMC,Amsterdam,Netherlands;Department of Experimental Immunology, Amsterdam Infection & Immunity Institute,Amsterdam UMC,Amsterdam,Netherlands
,
Joseph A Fraietta
Affiliations:
Center for Cellular Immunotherapies,University of Pennsylvania,Philadelphia,United States;Department of Pathology and Laboratory Medicine,University of Pennsylvania,Philadelphia,United States
,
Tom Hofland
Affiliations:
Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam,Amsterdam UMC,Amsterdam,Netherlands;Department of Experimental Immunology, Amsterdam Infection & Immunity Institute,Amsterdam UMC,Amsterdam,Netherlands
,
Sanne Tonino
Affiliations:
Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam,Amsterdam UMC,Amsterdam,Netherlands;Department of Experimental Immunology, Amsterdam Infection & Immunity Institute,Amsterdam UMC,Amsterdam,Netherlands
,
Eric Eldering
Affiliations:
Department of Experimental Immunology, Amsterdam Infection & Immunity Institute,Amsterdam UMC,Amsterdam,Netherlands
,
Mark-David Levin
Affiliations:
Department of Internal Medicine,Albert Schweitzer Hospital,Dordrecht,Netherlands
,
Peter J. Siska
Affiliations:
Department of Internal Medicine III,University Hospital Regensburg,Regensburg,Germany
,
Sanne Endstra
Affiliations:
Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam,Amsterdam UMC,Amsterdam,Netherlands;Department of Experimental Immunology, Amsterdam Infection & Immunity Institute,Amsterdam UMC,Amsterdam,Netherlands
,
Jeffrey C Rathmell
Affiliations:
Vanderbilt Center for Immunobiology, Departments of Pathology, Microbiology, and Immunology, Cancer Biology,Vanderbilt University Medical Center,Nashville,United States
,
Carl H June
Affiliations:
Center for Cellular Immunotherapies,University of Pennsylvania,Philadelphia,United States;Department of Pathology and Laboratory Medicine,University of Pennsylvania,Philadelphia,United States
,
David L Porter
Affiliations:
Department of Pathology and Laboratory Medicine,University of Pennsylvania,Philadelphia,United States
,
J. Joseph Melenhorst
Affiliations:
Center for Cellular Immunotherapies,University of Pennsylvania,Philadelphia,United States;Department of Pathology and Laboratory Medicine,University of Pennsylvania,Philadelphia,United States
,
Gerritje J. W. van der Windt
Affiliations:
Department of Experimental Immunology, Amsterdam Infection & Immunity Institute,Amsterdam UMC,Amsterdam,Netherlands;Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam,Amsterdam UMC,Amsterdam,Netherlands
Arnon P. Kater
Affiliations:
Department of Experimental Immunology, Amsterdam Infection & Immunity Institute,Amsterdam UMC,Amsterdam,Netherlands;Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam,Amsterdam UMC,Amsterdam,Netherlands
EHA Library. van Bruggen J. Jun 15, 2019; 266751; PS1134
Jaco van Bruggen
Jaco van Bruggen
Contributions
Abstract

Abstract: PS1134

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background

Chronic lymphocytic leukemia (CLL) patients acquire T cell dysfunction through a yet unresolved mechanism, impeding efficacy of immunotherapeutic strategies. As T cell function and development share an intricate relationship with T cell metabolism, we hypothesized that CLL cells impose a reduction in mitochondrial fitness and altered glucose metabolism on T cells, which may underlie the acquired T cell dysfunction.

Aims

We aim to elucidate the underlying mechanism of T cell dysfunction in CLL and intend to resolve metabolic dysfunction via pharmacological intervention.

Methods

We selected untreated CLL patients with a WBC greater than 20×109 cells/L. Age-matched healthy donors (HD) were used as controls. CAR T cells were obtained from the University of Pennsylvania, generated from relapsed/refractory (R/R) CLL patients enrolled in two clinical trials of single-agent CTL019 therapy (registered at clinicaltrials.gov; NCT01029366, and NCT01747486). We either directly analyzed T cells by flow cytometry or XF96 Seahorse, or after a 2 day culture with or without CD3 and CD28 antibodies.

Results

We have previously shown that stimulated CLL derived CD8+ T cells had reduced expression of activation markers, increased expression of PD-1 and reduced expression of glucose transporter GLUT-1, coinciding with reduced glucose uptake. In addition we observed that mitochondrial biogenesis is impaired in CLL derived CD8+ T cells. Clinical significance of this data was further demonstrated by analyzing mitochondrial mass of CAR T cells from CLL patients showing complete response (CR) versus patients with no response (NR). Patients with CR had higher mitochondrial mass compared to NR. These findings support our hypothesis that CLL cells reprogram T cell metabolism, in particular mitochondrial fitness and biogenesis (Blood 2018, 132:235).

In this follow up study we investigated (A) whether metabolic reprogramming is a pan T cell phenomenon or CD8 specific, (B) upstream signaling leading to metabolic reprogramming, and (C) if pharmacological intervention can boost T cell metabolism and thereby function. We found that (A) CD4 T cells share most metabolic alterations with CD8 T cells in CLL, and that (B) AKT signaling is disturbed in CLL T cells. For the metabolic interventions studies (C) we are currently exploring the effects of manipulating mitochondrial ROS or respiration, and blocking immune-suppressive cytokines. Results of both approaches will be presented at the conference

Conclusion

We found that metabolic impairment in CLL T cells is not restricted to CD8 T cells, but also applies to CD4 T cells, and that impaired AKT signaling is at least part of the upstream bottleneck. We are currently investigating the use of compounds and metabolites in order to improve mitochondrial fitness of T cells for CLL patients to benefit autologous immunotherapies.

 

Session topic: 5. Chronic lymphocytic leukemia and related disorders - Biology & Translational Research

Keyword(s): MTOR

By continuing to browse or by clicking “Accept Terms & all Cookies”, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies