Existing drug may help improve responses to cellular therapies in
advanced leukemias

Date:
August 16, 2021
Source:
University of Pennsylvania School of Medicine
Summary:
A new study shows how to overcome resistance to CAR T cell therapy
with an experimental small molecule inhibitor.



FULL STORY ==========================================================================
Too many "exhausted" T cells left in the wake of aggressive chemotherapy regimens for patients with advanced chronic lymphocytic leukemia
(CLL) make it more challenging for chimeric antigen receptor (CAR)
T cell therapy to do its job. Now, a new study from researchers in the
Perelman School of Medicine at the University of Pennsylvania shows how
to overcome this type of resistance and reinvigorate these T cells with
an experimental small molecule inhibitor.


========================================================================== Reporting online today in the Journal of Clinical Investigation, the
team shows how the drug, known as JQ1, improved CAR T cell function by inhibiting what is known as the bromodomain and extra terminal (BET)
proteins. BET, the researchers showed, can disrupt CAR expression and
key acetylated histone functions in T cells in CLL.

The findings demonstrate, for the first time, this mechanism of resistance
and present a much-needed target for CLL when treating patients with
cellular therapies like CAR. Only a small subset of patients with advanced
CLL respond to CAR T cell therapy -- compared to 80 percent of acute lymphocytic leukemia patients with advanced disease.

"Why CAR T cells fail to fully attack cancer cells in so many CLL
patients is an important question that needs to be answered in order
to expand the use of these immunotherapies in CLL and other cancers,"
said senior author Joseph A.

Fraietta, PhD, an assistant professor of Microbiology at Penn, and
member of the Center for Cellular Immunotherapies. "Treating these
'war weary' T cells during the CAR T cell engineering process has the
potential to boost responses, we've shown here. It's setting the stage
for a very promising set of next steps that rationalize further studies, including clinical trials, to prove this approach is safe and feasible."
Using the small molecule inhibitor and the T cells and CD19 CAR T cells
from multiple previously treated patients, the researchers demonstrated
that the BET protein plays a role in downregulating CAR expression, and
that, if blocked, can diminish CAR cell T cell exhaustion and increase
the production of CAR T cells from CLL patients with poor lymphocytes.

Treatment with JQ1 also increased levels of various immunoregulatory
cytokines and chemokines previously reported to be produced by CAR T
cells in CLL during successful therapy. The array of native immune and
CAR cells mirrored those found more typically in patients who do respond.

Given this observed reinvigoration of dysfunctional CLL patient CAR T
cells by BET inhibition, the authors suggest that incorporating JQ1 into cellular engineering and expansion processes could lead to a generation
of less defective and more potent final CAR T cells for patients.

To what extent the above pathways contribute to the effects of JQ1 on
CAR T cells is a focus of ongoing investigations for the research group.

"This work shows us that T cells can be taught new tricks," said Bruce
Levine, PhD, the Barbara and Edward Netter Professor in Cancer Gene
Therapy in Penn's Perelman School of Medicine, and co-author on the
study. "That is to say that the methods of manufacturing can be adapted
to improve CAR T cell function, so that what would have been exhausted
or dysfunctional cells can now be reinvigorated, and potentially lead
to better clinical responses in more patients than before." This work
was supported by the Bob Levis Funding Group, along with the National
Institute of Allergy and Infectious Diseases (T32 AI007632), National
Cancer Institute (P01 CA214278 575, R01 CA241762 U54 CA244711 576,
P30 CA016520-44S3, and P30 CA016520-44S4), National Institute on Aging
(U01 AG066100), the National Institute of General Medical Sciences (R01 GM118501), an Emerging Cancer Informatics Center of Excellence award
from the Penn Institute for Biomedical Informatics and Abramson Cancer
Center, Gabrielle's Angel Foundation, an Alliance for Cancer Gene Therapy Investigator Award in Cell and Gene Therapy for Cancer, and Novartis.

========================================================================== Story Source: Materials provided by University_of_Pennsylvania_School_of_Medicine. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Weimin Kong, Alexander Dimitri, Wenliang Wang, In-Young Jung,
Christopher
J. Ott, Maria Fasolino, Yan Wang, Irina Kulikovskaya, Minnal Gupta,
Todd Yoder, Jamie E. DeNizio, John K. Everett, Erik F. Williams,
Jun Xu, John Scholler, Tyler J. Reich, Vijay G. Bhoj, Kathleen
M. Haines, Marcela V.

Maus, J. Joseph Melenhorst, Regina M. Young, Julie K. Jadlowsky,
Katherine T. Marcucci, James E. Bradner, Bruce L. Levine, David L.

Porter, Frederic D. Bushman, Rahul M. Kohli, Carl H. June, Megan M.

Davis, Simon F. Lacey, Golnaz Vahedi, Joseph A. Fraietta. BET
bromodomain protein inhibition reverses chimeric antigen receptor
extinction and reinvigorates exhausted T cells in chronic
lymphocytic leukemia. Journal of Clinical Investigation, 2021;
131 (16) DOI: 10.1172/JCI145459 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210816132103.htm

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