Science Spotlight

Cytokines may give CD19 CAR-T cells a boost

From the Turtle Laboratory, Clinical Research Division

Lymphomas are a diverse group of cancers which arise from B or T cells. These cancerous cells proliferate uncontrollably and can ultimately overwhelm hematopoietic and lymphoid tissues. B-cell non-Hodgkin lymphomas (NHL) commonly express CD19, a marker which may be targeted by immunotherapies. One immunotherapy showing very promising results utilizes T cells genetically engineered to express a CD19-specific chimeric antigen receptor (CAR). CD19 CARs contain an extracellular antibody fragment targeting CD19 that allows the CAR-T cells to bind specifically to cancerous cells expressing CD19. The antibody fragment is connected to an intracellular signaling domain with one or more costimulatory signaling receptors that facilitates activation and proliferation of the CAR-T cells once CD19-expressing cells are encountered.

Two CD19 CAR-T cell products, axicabtagene ciloleucel and tisagenlecleucel, are currently FDA-approved for the treatment of aggressive B-cell Non-Hodgkin Lymphoma, or NHL. At Fred Hutch, more than 180 patients with relapsed/refractory B-cell malignancies have been treated with CD19 CAR-T cells in a phase 1/2 clinical trial. The laboratory of Dr. Cameron Turtle sought to determine why some patients fail to respond or have higher risk of relapse after CD19 CAR-T cell therapy and how this therapy can be improved. Led by Post-Doctoral Research Fellow Dr. Alexandre Hirayama, they published a study in the journal Blood. Dr. Hirayama elaborated on why they conducted the study: “In conjunction with the heterogeneity of patients undergoing CAR-T cell immunotherapy for NHL, an enduring problem for the field is that multivariable analyses of factors that are independently associated with initial response or durable remission have not been reported. This failure has hindered the identification of patients at high risk of relapse and development of novel strategies to improve outcomes. Our study provides the first multivariable analyses of response and progression free survival in adults with aggressive B-cell NHL treated with CD19 CAR-T cell immunotherapy.”

Patients enrolled in the study were diagnosed with relapsed/refractory aggressive B-cell NHL and received either low or high-intensity lymphodepleting chemotherapy consisting of cyclophosphamide and fludarabine (Cy/Flu). Two to four days after chemotherapy, the patients were infused with CD19 CAR-T cells. The patients had response assessment approximately 4 weeks after CAR-T cell infusion and those with no evidence of disease by PET-CT were considered to have achieved complete remission (CR). The authors found that CR was associated with improved progression-free survival (PFS) and overall survival, and therefore decided to examine the factors that influence CR. They identified that a greater increase in serum concentration of the cytokine monocyte chemoattractant protein-1 (MCP-1) from before lymphodepletion to the day of infusion (day 0) was an important factor that correlated with CR. The team also found that a higher serum concentration of MCP-1 on day 0 was associated with superior PFS. In addition, they showed that high serum levels of the cytokine IL-7 correlated with better PFS. As IL-7 is involved in T-cell survival and effector function, it may be acting on CAR-T cells to promote their ability to persist in fighting cancerous cells. Dr. Hirayama said, “The finding that a favorable cytokine profile after lymphodepletion is strongly associated with durable PFS has profound implications for the design of strategies to supplement key cytokines or augment the cytokine response to lymphodepletion and will guide the development of novel approaches to CAR-T cell immunotherapy for NHL.”

A Kaplan-Meier curve of progression-free survival (PFS) in patients who received high-intensity lymphodepletion and did or did not achieve a favorable cytokine profile (day 0 MCP-1 and peak IL-7 > median), and in those who received low-intensity lymphodepletion. Cytokine concentrations after lymphodepletion are better associated with PFS than the intensity of Cy/Flu lymphodepletion.
A Kaplan-Meier curve of progression-free survival (PFS) in patients who received high-intensity lymphodepletion and did or did not achieve a favorable cytokine profile (day 0 MCP-1 and peak IL-7 > median), and in those who received low-intensity lymphodepletion. Cytokine concentrations after lymphodepletion are better associated with PFS than the intensity of Cy/Flu lymphodepletion. Image provided by Dr. Alexandre Hirayama

The Turtle lab would like to further explore how MCP-1 and IL-7 contribute to the antitumor response. Dr. Hirayama said, “Particularly for MCP-1, additional studies are needed to characterize the mechanisms by which MCP-1 is associated with better CAR-T cell expansion or effector function. Additionally, high tumor-derived MCP-1 has been shown to elicit tumor tropism of adoptively transferred T cells in vivo, which raises the interest of studying the tumor microenvironment in NHL patients treated with CD19 CAR-T cell immunotherapy.”

 

 

 

This work was supported by the National Institutes of Health, Life Science Discovery Fund, Bezos Family, the University of British Columbia Clinician Investigator Program, FHCRC Immunotherapy Integrated Research Center, and Juno Therapeutics/Celgene, Inc.

Fred Hutch/UW Cancer Consortium members Qian Wu, Ted Gooley, Ryan Cassaday, Aude Chapuis, Tejaswini Dhawale, Paul Hendrie, Hans-Peter Kiem, Ryan Lynch, Mazyar Shadman, Brian Till, Stanley Riddell, David Maloney, and Cameron Turtle contributed to this research.              

Hirayama AV, Gauthier J, Hay KA, Voutsinas JM, Wu Q, Gooley T, Li D, Cherian S, Chen X, Pender BS, Hawkins RM, Vakil A, Steinmetz RN, Acharya UH, Cassaday RD, Chapuis AG, Dhawale TM, Hendrie PC, Kiem HP, Lynch RC, Ramos J, Shadman M, Till BG, Riddell SR, Maloney DG, Turtle CJ. 2019. The response to lymphodepletion impacts PFS in aggressive non-Hodgkin lymphoma patients treated with CD19 CAR-T cells. Blood. 2019 Feb 19. doi: 10.1182/blood-2018-11-887067. [Epub ahead of print]

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