Treatment of secondary CNS lymphoma using CD19-targeted chimeric antigen receptor (CAR) T cells

Kathryn Kline; Tim Luetkens; Rima Koka; Michael E Kallen; Wengen Chen; Haroon Ahmad; Destiny Omili; Thierry Iraguha; Etse Gebru; Xiaoxuan Fan; Alexis Miller; Nishanthini Dishanthan; Jillian M Baker; Kenneth A Dietze; Kim G Hankey; Jean A Yared; Nancy M Hardy; Aaron P Rapoport; Saurabh Dahiya; Djordje Atanackovic

doi:10.1007/s00262-023-03619-9

Treatment of secondary CNS lymphoma using CD19-targeted chimeric antigen receptor (CAR) T cells

Cancer Immunol Immunother. 2024 Feb 13;73(3):45. doi: 10.1007/s00262-023-03619-9.

Authors

Kathryn Kline^{1

2}, Tim Luetkens^{1

2

3}, Rima Koka⁴, Michael E Kallen⁴, Wengen Chen⁵, Haroon Ahmad^{1

6}, Destiny Omili^{1

7}, Thierry Iraguha^{1

7}, Etse Gebru^{1

7}, Xiaoxuan Fan^{1

3}, Alexis Miller⁴, Nishanthini Dishanthan^{1

7}, Jillian M Baker³, Kenneth A Dietze³, Kim G Hankey^{1

2}, Jean A Yared^{1

2

7}, Nancy M Hardy^{1

2

7}, Aaron P Rapoport^{1

2

7}, Saurabh Dahiya^{1

2

7

8}, Djordje Atanackovic^#^{9

10

11

12}

Affiliations

¹ Cancer Immunotherapy, Fannie Angelos Cellular Therapeutics GMP Laboratory, University of Maryland Greenebaum Comprehensive Cancer Center, Bressler Research Building, Room 9-011, 655 W. Baltimore Street, Baltimore, MD, 21201, USA.
² Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
³ Department of Microbiology and Immunology, University of Maryland, Baltimore, MD, USA.
⁴ Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA.
⁵ Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
⁶ Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
⁷ Transplant and Cellular Therapy Program, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.
⁸ Stanford University, Stanford, CA, USA.
⁹ Cancer Immunotherapy, Fannie Angelos Cellular Therapeutics GMP Laboratory, University of Maryland Greenebaum Comprehensive Cancer Center, Bressler Research Building, Room 9-011, 655 W. Baltimore Street, Baltimore, MD, 21201, USA. datanackovic@som.umaryland.edu.
¹⁰ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA. datanackovic@som.umaryland.edu.
¹¹ Department of Microbiology and Immunology, University of Maryland, Baltimore, MD, USA. datanackovic@som.umaryland.edu.
¹² Transplant and Cellular Therapy Program, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA. datanackovic@som.umaryland.edu.

^# Contributed equally.

Abstract

Background: Aggressive B cell lymphoma with secondary central nervous system (CNS) involvement (SCNSL) carries a dismal prognosis. Chimeric antigen receptor (CAR) T cells (CAR-T) targeting CD19 have revolutionized the treatment for B cell lymphomas; however, only single cases with CNS manifestations successfully treated with CD19 CAR-T have been reported.

Methods: We prospectively enrolled 4 patients with SCNSL into our study to assess clinical responses and monitor T cell immunity.

Results: Two of four SNCSL patients responded to the CD19-targeted CAR-T. Only one patient showed a substantial expansion of peripheral (PB) CAR-T cells with an almost 100-fold increase within the first week after CAR-T. The same patient also showed marked neurotoxicity and progression of the SNCSL despite continuous surface expression of CD19 on the lymphoma cells and an accumulation of CD4⁺ central memory-type CAR-T cells in the CNS. Our studies indicate that the local production of chemokine IP-10, possibly through its receptor CXCR3 expressed on our patient's CAR-T, could potentially have mediated the local accumulation of functionally suboptimal anti-tumor T cells.

Conclusions: Our results demonstrate expansion and homing of CAR-T cells into the CNS in SNCSL patients. Local production of chemokines such as IP-10 may support CNS infiltration by CAR-T cells but also carry the potential of amplifying local toxicity. Future studies investigating numbers, phenotype, and function of CAR-T in the different body compartments of SNSCL patients receiving CAR-T will help to improve local delivery of "fit" and highly tumor-reactive CAR-T with low off-target reactivity into the CNS.

Keywords: B cell lymphoma; CAR-T cells; CNS lymphoma; Cytokines; Neurotoxicity; T cells.

MeSH terms

Antigens, CD19
Central Nervous System Neoplasms* / therapy
Chemokine CXCL10
Humans
Lymphoma*
Receptors, Chimeric Antigen*

Substances

Receptors, Chimeric Antigen
Chemokine CXCL10
Antigens, CD19

Grants and funding

P30 CA134274/CA/NCI NIH HHS/United States