Inhibitor drug entinostat `primes' the body to better respond to anti-
cancer treatment with immunotherapy

Date:
August 18, 2021
Source:
Johns Hopkins Medicine
Summary:
Combining a histone deacetylase inhibitor drug with immunotherapy
agents has been deemed safe, and may benefit some patients with
advanced cancers that have not responded to traditional therapy,
according to results of a phase 1 clinical trial.



FULL STORY ========================================================================== Combining a histone deacetylase inhibitor drug with immunotherapy agents
is safe, and may benefit some patients with advanced cancers that have
not responded to traditional therapy, according to results of a phase
1 clinical trial led by researchers at the Johns Hopkins Kimmel Cancer
Center, Bloomberg~Kimmel Institute for Cancer Immunotherapy and several
other centers including University of Pittsburgh Cancer Institute, Yale
Cancer Center and City of Hope in Los Angeles, which participated in
study enrollment, and the University of Southern California and University College Cork in Ireland, which collaborated on analysis of the data.


========================================================================== During the study, 33 patients with advanced solid tumors received the
histone deacetylase inhibitor drug entinostat for two weeks. Then,
some patients received the immunotherapy agent nivolumab, a checkpoint inhibitor, in combination with the entinostat, while others received
both nivolumab and a second checkpoint inhibitor agent, ipilimumab,
after the initial dosing with entinostat.

Checkpoint inhibitors, such as nivolumab and ipilimumab, release important "brakes" that permit the immune system to fight the cancer cells. The epigenetic inhibitor drug entinostat has been shown in preclinical models
and laboratory studies (which led to this current clinical trial) to drive changes in the chemical environment of cells to make them more amenable
to immunotherapy, says Vered Stearns, M.D., director of the Women's Malignancies Disease Group at the Johns Hopkins Kimmel Cancer Center.

The authors found that the objective response rate, or percentage of
patients whose cancer responded to therapy, was 16%. One patient with triple-negative breast cancer had a complete response, meaning a total shrinkage of the cancer.

Because the cancer types included in the study are not felt to have high response rates to immune checkpoint therapy, these preliminary results are
very promising. Treatment-related adverse events were mostly low grade,
and included fatigue, nausea, anemia and diarrhea.

These results were published online in the June 16 issue of Clinical
Cancer Research.

Study co-author Evanthia T. Roussos Torres, M.D., Ph.D., an adjunct
professor at Johns Hopkins and assistant professor of medicine at the University of Southern California's Norris Comprehensive Cancer Center in
Los Angeles, says the entinostat functioned as an immune system-priming
agent prior to using immunotherapy in solid tumors that traditionally
are nonresponsive to checkpoint inhibition therapy.



==========================================================================
"One of the major findings of our study is that this is a safe and
tolerable combination of therapies," she says. "There aren't very many
trials investigating dual immune checkpoint inhibition in combination
with other novel therapeutics. We determined a safe, tolerable dose with
this combination that had very few adverse effects. That is significant."
The researchers collected blood and tumor samples from the 33 patients
before and after the two weeks of entinostat to assess the impact of the entinostat on the immune system, and also after the addition of the immune checkpoint agents to evaluate the effect of each of the treatments on
the immune environment. The study team found a significant increase in
the ratio of CD8/FoxP3 gene expression in tumors following checkpoint
inhibitor treatment but not after entinostat treatment alone. This
suggests that the combination therapy helped increase both cytotoxic
immune system T cells -- immune cells that directly kill cancer cell --
as well as decrease immune system T regulatory cells - - immune cells
that modulate the immune response -- which equaled a stronger immune
response, Roussos Torres says.

The median age of participants was 60, most (91%) were female, 30% had
breast cancer (the main tumor type studied) and the median number of prior regimens tried for their disease was 3.5. The median progression-free
survival, or time until disease progression or death, was 6.1 months,
and median overall survival was 10.6 months. Stable disease, considered
the best response, was observed in 44% of participants. Clinical benefit
rate, or the percentage of patients who achieved stable disease, or
partial or complete response, was 60%.

The most robust increases in CD8/FoxP3 ratio were observed in two patients
with HR-positive breast cancer who experienced a partial response and
stable disease. Three additional patients who experienced stable disease
had adenocarcinoma, a cancer of glandular tissue.

The complete response in a patient with breast cancer "is a promise that
there may be a role for this combination of therapies in breast cancers,"
says senior study author Roisin M. Connolly, M.B.B.Ch., M.D., an adjunct professor at Johns Hopkins and chair in cancer research at University
College Cork and Cork University Hospital in Ireland. "Immunotherapy
hasn't been as big a blockbuster to date in advanced breast cancer as
in other cancers, such as lung cancers or melanoma. This study paves
the way for novel combination therapies that have the potential to
improve response rates to immune checkpoint inhibitors in traditionally less-responsive tumor types." This drug combination is being investigated further in a group of 24 patients with HER2-negative breast cancer as
part of the same NCI-sponsored clinical trial. "We are excited to have completed accrual to these ongoing studies in advanced HER2-negative
breast cancer, and expect to report on these findings later this year,"
says Stearns.

Study co-authors were Christine Rafie, Chenguang Wang, David Lim, Melinda Downs, Molly Geare, Leslie Anforth, Michelle A. Rudek, Qingfeng Zhu,
Sepideh Besharati, Ashley Cimino-Mathews, Robert A. Anders, Vered Stearns,
and Elizabeth M. Jaffee of Johns Hopkins. Other authors contributing to
the study were from the University of Miami Miller School of Medicine;
the University of Pittsburgh Cancer Institute; Yale Cancer Center; City
of Hope, Duarte, California; the National Cancer Institute; and the NIH Clinical Center.

The work was supported by the National Cancer Institute (grants
P30CA006973, P30CA014089, UM1CA186689, UM1CA186690, U24CA247648, and UM1CA186717); as well as NIH grants to the Bloomberg~Kimmel Institute
for Immunotherapy, Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (grants P30CA006973
and UL1 TR001079), the Shared Instrument Grant (1S10RR026824-01),
the Clinical Protocol and Data Management facilities (P30 CA006973 and P30CA047904). Support was also provided by the Commonwealth Foundation,
the National Comprehensive Cancer Network, the Mary Kay Foundation,
the V Foundation, and the Tower Cancer Research Foundation.

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


========================================================================== Journal Reference:
1. Evanthia T Roussos Torres, Christine I Rafie, Chenguang Wang,
David Lim,
Adam M Brufsky, Patricia M. LoRusso, Joseph Paul Eder, Vincent
Chung, Melinda Downs, Molly Geare, Richard L Piekarz, Howard
Streicher, Leslie Anforth, Michelle A. Rudek, Qingfeng Zhu, Sepideh
Besharati, Ashley Cimino-Mathews, Robert A. Anders, Vered Stearns,
Elizabeth M. Jaffee, Roisin M Connolly. Phase 1 Study of Entinostat
and Nivolumab with or without Ipilimumab in Advanced Solid Tumors
(ETCTN-9844). Clinical Cancer Research, 2021; clincanres.5017.2021
DOI: 10.1158/1078-0432.CCR-20-5017 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210818130541.htm

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