Experimental drug that boosts immunotherapy shows promise in bladder
cancer study

Date:
August 16, 2021
Source:
UNC Lineberger Comprehensive Cancer Center
Summary:
Researchers have found adding the experimental drug entinostat
to an immunotherapy-like treatment substantially boosted cancer
remission in mice. This approach shows such promise that it's
already being tested in an ongoing clinical trial in people with
advanced bladder cancer.



FULL STORY ==========================================================================
A new study in mice found that adding the experimental drug entinostat
to an immunotherapy-like treatment substantially boosted cancer
remission. This approach shows such promise that it's already being tested
in an ongoing clinical trial in people with advanced bladder cancer.


==========================================================================
This finding, led by scientists at the University of North Carolina
Lineberger Comprehensive Cancer Center, was published August 16, 2021,
in the Journal of Clinical Investigation.

"Bladder cancer rates in the United States have been stable or decreasing slightly over the past decade, but five-year survival rates have barely
budged since the 1990s," said UNC Lineberger's William Y. Kim, MD, Rush
S. Dickson Distinguished Professor of Medicine and professor of Genetics
and the paper's co-corresponding author. "Hence our search for ways to
improve treatments for a cancer that can be extremely difficult to treat
in its advanced stages." The FDA recently approved several immunotherapy treatments for bladder cancer, but these treatments shrink tumors in only approximately 15 percent of patients. With the goal of boosting response
rates to immunotherapies, the researchers turned to histone deacetylase
(HDAC) inhibitors in hopes that this class of drugs would result in
expression of the immunotherapy targets that had previously been silenced during tumor evolution. In this study, the researchers used entinostat,
a highly selective HDAC inhibitor being tested in late-stage clinical
trials in various types of cancer.

"Importantly, neoantigen-specific T cells were increased in number after entinostat treatment. This means that the antigens unmasked by entinostat
can be targeted by T cells already in the body that otherwise would
not be activated to kill tumor cells," said UNC Lineberger's Benjamin
Vincent, MD, assistant professor at the UNC School of Medicine and co-corresponding author.

"We are excited about combining entinostat with therapies that boost T
cell function in the future." When treated with entinostat in combination
with immunotherapy, two-thirds of mice had a complete disappearance of
their tumors and none of the mice had relapse of their tumors when taken
off the treatment.

"Use of entinostat alone in people has not led to effective reductions
in tumor size," said UNC Lineberger's Tracy Rose, MD, MPH, assistant
professor at the UNC School of Medicine. "We believe that neoantigens
have to be unmasked, or made visible, at the same time that the brakes
on T cells are released by immunotherapies." Given the clear benefits
of adding entinostat to immunotherapy in the lab, the investigators
are conducting a clinical trial to test the benefit of the combination
therapy with people who have advanced bladder cancer. That trial started
in 2020 and its findings are expected to be reported in late 2022
(Clinical trial NCT03978624).

"For our next steps, we will wait until next year to see if the clinical results look promising, and if so, we will consider a larger trial,"
concluded Kim. "In the meantime, we would like to continue to improve
the therapy and personalize it by adding a strategy called neoantigen vaccination to the entinostat plus immunotherapy regimen, to boost even
further the chances for successful outcomes." Authors and disclosures
In addition to Kim, Rose, and Vincent the paper's other authors at UNC
include Andrew S. Truong, Mi Zhou, PhD, Bhavani Krishnan, PhD, Takanobu
Utsumi, MD, PhD, Ujjawal Manocha, MS, Kyle G. Stewart, Wolfgang Beck,
Matthew I. Milowsky, MD, Xiaping He, Christof C. Smith, MD, PhD, Lisa
M. Bixby, MS, Charles M.

Perou, PhD, Sara E. Wobker, MD, MPH, and Sean T. Bailey, PhD, This work
was supported by the University Cancer Research Fund to Kim and Vincent, American Cancer Society grant RSG-14-219-01-TBG to Kim, an NCI R01-
CA241810 grant to Kim and Vincent, the Uhera Foundation to Utsumi, and an
NCI F31 CA247250 to Truong. Rose is supported by an NCI K08CA248967 grant
as well as the Doris Duke Charitable Foundation grant 2015213). Vincent
was supported by an NIH K12 Career Development Award in Clinical Oncology grant, 5K12CA120780.

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


========================================================================== Journal Reference:
1. Andrew S. Truong, Mi Zhou, Bhavani Krishnan, Takanobu Utsumi,
Ujjawal
Manocha, Kyle G. Stewart, Wolfgang Beck, Tracy L. Rose, Matthew I.

Milowsky, Xiaping He, Christof C. Smith, Lisa M. Bixby, Charles
M. Perou, Sara E. Wobker, Sean T. Bailey, Benjamin G. Vincent,
William Y. Kim.

Entinostat induces antitumor immune responses through immune
editing of tumor neoantigens. Journal of Clinical Investigation,
2021; 131 (16) DOI: 10.1172/JCI138560 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210816125723.htm

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