Novel immunotherapy agent safe, shows promise against high-risk prostate cancers

Date:
April 10, 2023
Source:
Johns Hopkins Medicine
Summary:
A new drug, a monoclonal antibody known as enoblituzumab, is safe
in men with aggressive prostate cancer and may induce clinical
activity against cancer throughout the body, according to a phase
2 study. If confirmed in additional studies, enoblituzumab could
become the first promising antibody-based immunotherapy agent
against prostate cancer.


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FULL STORY ==========================================================================
A new drug, a monoclonal antibody known as enoblituzumab, is safe in
men with aggressive prostate cancer and may induce clinical activity
against cancer throughout the body, according to a phase 2 study led
by investigators at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy. If confirmed in
additional studies, enoblituzumab could become the first promising antibody-based immunotherapy agent against prostate cancer.


==========================================================================
In a clinical trial, 32 men with high-risk or very high-risk prostate
cancers who were scheduled for prostate cancer surgery were treated
with six weekly infusions of enoblituzumab prior to surgery, and were
followed for an average of 30 months thereafter. Twenty-one patients,
or 66%, had an undetectable prostate-specific antigen (PSA) level
12 months following surgery, suggesting that there was no sign of
residual disease. Additionally, the drug was well- tolerated overall;
no patients had any surgical delays or medical complications during or
after the operation.

A description of the work was published April 3 in the journal Nature
Medicine.

If enoblituzumab continues to perform well in further larger randomized studies, it could represent a new pathway for immunotherapy against
multiple cancers, and the first one that may have a role for prostate
cancer, says lead study author and cancer immunology researcher
Eugene Shenderov, M.D., Ph.D., assistant professor of oncology at
the Johns Hopkins University School of Medicine. Other existing
antibody-based immunotherapy drugs have targeted immune checkpoints,
natural on/off switches mediating immune responses, such as CTLA-4,
PD-1 and LAG-3. Cancer cells hijack these checkpoints, turning off the
immune response to cancer. "Drugs that block these checkpoints have had
success in other types of cancers, including lung cancer and melanoma,
but not in prostate cancer," says Shenderov.

Enoblituzumab works by binding to a protein called B7-H3 that is
overexpressed on prostate cancer cells and believed to impede the immune system's ability to attack cancer cells. The new therapy could pack
a one-two punch against cancer, Shenderov says, by blocking B7-H3's
inhibition of the immune system's recognition and elimination of cancer
cells, and also triggering a process called antibody-dependent cellular cytoxicity (ADCC), which leads to tumor cell destruction by activating additional immune cells such as macrophages and natural killer cells.

"Enoblituzumab appears safe and seems to activate the immune system in a
way that involves both T-cells and myeloid cells," Shenderov says. "What
this means is if these results can be replicated in a larger, randomized
study, it opens the possibility that combining this therapy with local, curative-intent therapies like surgical prostate removal or radiation
therapy, would allow this drug to potentially kill micrometastatic disease hiding elsewhere in the body, and therefore prevent a significant number
of men from experiencing recurring disease. That could be a paradigm
shift in prostate cancer." The median age of study participants was 64
(age range 48-74). About half (47%) had a PSA greater than 10 ng/mL at diagnosis, which is abnormally high, and 50% had Gleason grade group
5 at biopsy, meaning they had highly aggressive disease. Patients were
enrolled from February 2017 through June 2019.

Enoblituzumab was confirmed to penetrate into prostate tumors and to
bind to B7-H3 in the vast majority of participants, according to prostate samples studied after surgery.

Side effects of enoblituzumab were generally mild and included fatigue, neurological symptoms such as headache or dizziness, and flu-like or cold symptoms. One patient developed inflammation of the heart (myocarditis),
which fully resolved with steroid treatment, and is a known side effect
of other immune checkpoint drugs.

Beyond safety and anti-tumor activity based on PSA dropping to
undetectable levels, investigators also looked for changes in the tumor microenvironment before and after enoblituzumab treatment. They found
increased markers of cytotoxicity after treatment, consistent with the
concept that the immune system was activated against tumor cells. The
tumors showed increased infiltration with granulocytes, leukocytes and
effector T-cells, and there was roughly a doubling of the density of
cytotoxic T cells after treatment.

"The findings are exciting but exploratory, and need to be confirmed
in larger study cohorts," cautions senior study author Emmanuel
S. Antonarakis, M.D., the Clark Endowed Professor of Medicine and
director of GU Oncology for the University of Minnesota Masonic Cancer
Center. Antonarakis was the senior investigator of the study while he
was at the Johns Hopkins Kimmel Cancer Center.

"However, these results in high-risk prostate cancer patients, and the
broader need for immunotherapeutic strategies with efficacy in prostate cancers, provide justification to further develop multipronged approaches
that include targeting B7-H3 to optimize antitumor activity in prostate
cancers and other solid malignancies," he says.

Investigators are now planning a larger, randomized trial of enoblituzumab
in newly diagnosed prostate cancer patients to assess clinical activity
of the drug compared to current standards of care.

Coauthors of the current study were Angelo M. De Marzo, Tamara L. Lotan,
Hao Wang, Sin Chan, Su Jin Lim, Hogkai Ji, Mohamad El Allaf, Carolyn
Chapman, Samuel R. Denmeade, Kenneth J. Pienta, Christian P. Pavlovich,
and Drew M.

Pardoll of Johns Hopkins. Other study authors contributing to the
paper were from MacroGenics Inc. of Rockville, Maryland (the maker
of enoblituzumab); NanoString Technologies Inc. of Seattle; Adaptive Biotechnologies of Seattle; CDI Labs of Baltimore; the Northwestern
University Feinberg School of Medicine in Chicago; and Charles G. Drake formerly at Johns Hopkins, who currently leads Immuno-Oncology at Janssen Research and Development.

The work was supported by the National Institutes of Health (Cancer Center Support Grant P30 CA006973), an NCI SPORE in Prostate Cancer (P50CA58236),
a Prostate Cancer Foundation Young Investigator Award, the Department
of Defense (grants W81XWH-16-PCRP-CCRSA and W81XWH-18-2-0015), and the Bloomberg~Kimmel Institute for Cancer Immunotherapy and by Macrogenics
Inc, of Rockville, Maryland.

E. Shenderov is a paid consultant to GT Biopharma, Guidepoint Global, FirstThought, GLG, and receives institutional research funding from
MacroGenics Inc., manufacturer of enoblituzumab. These relationships are managed by The Johns Hopkins University in accordance with its conflict
of interest policies.

E. Antonarakis has served as a paid consultant for Janssen, Astellas,
Sanofi, Bayer, Bristol Myers Squibb, Amgen, Constellation, Blue Earth,
Exact Sciences, Invitae, Curium, Pfizer, Merck, AstraZeneca, Clovis and
Eli Lilly; and has received research support from MacroGenics, Janssen,
Johnson & Johnson, Sanofi, Bristol Myers Squibb, Pfizer, AstraZeneca,
Novartis, Curium, Constellation, Celgene, Merck, Bayer, Clovis and
Orion. These relationships are managed by the University of Minnesota (Antonarakis' current institution) in accordance with their conflict of interest policies.

* RELATED_TOPICS
o Health_&_Medicine
# Prostate_Cancer # Men's_Health # Urology # Cancer #
Colon_Cancer # Diseases_and_Conditions # Lymphoma #
Breast_Cancer
* RELATED_TERMS
o Prostate_cancer o Cervical_cancer
o Monoclonal_antibody_therapy o Colorectal_cancer o
Breast_cancer o Stomach_cancer o Metastasis o Ovarian_cancer

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


========================================================================== Journal Reference:
1. Eugene Shenderov, Angelo M. De Marzo, Tamara L. Lotan, Hao Wang, Sin
Chan, Su Jin Lim, Hongkai Ji, Mohamad E. Allaf, Carolyn Chapman,
Paul A.

Moore, Francine Chen, Kristina Sorg, Andrew M. White, Sarah
E. Church, Briana Hudson, Paul A. Fields, Shaohui Hu, Samuel
R. Denmeade, Kenneth J.

Pienta, Christian P. Pavlovich, Ashley E. Ross, Charles G. Drake,
Drew M.

Pardoll, Emmanuel S. Antonarakis. Neoadjuvant enoblituzumab in
localized prostate cancer: a single-arm, phase 2 trial. Nature
Medicine, 2023; DOI: 10.1038/s41591-023-02284-w ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/04/230410123651.htm

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