A new drug, a monoclonal antibody known as enoblituzumab, is safe in men with aggressive prostate cancer and may induce whole-body anticancer clinical activity, according to a phase 2 study led by researchers 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- or very-high-risk prostate cancer who were scheduled for prostate cancer surgery were treated with six weekly infusions of enoblituzumab before surgery and followed for an average of 30 months afterward. Twenty-one patients, or 66%, had an undetectable prostate-specific antigen (PSA) level 12 months after surgery, suggesting no signs of residual disease. In addition, the drug was generally well tolerated; no patient had surgical delays or medical complications during or after the operation.
A job description was published April 3 in the journal Natural medicine.
If enoblituzumab continues to do well in other, larger randomized trials, it could represent a new avenue for immunotherapy against multiple types of cancer, and the first that may have a role for prostate cancer, says the study’s lead author and investigator at cancer immunology, Eugene Shenderov, MD, 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 that mediate immune responses, such as CTLA-4, PD-1, and LAG-3. Cancer cells hijack these checkpoints, shutting down the immune response to cancer. “Drugs that block these checkpoints have been successful in other types of cancer, including lung cancer and melanoma, but not in prostate cancer,” Shenderov says.
Enoblituzumab works by binding to a protein called B7-H3 that is overexpressed in prostate cancer cells and is thought to impair the immune system’s ability to attack cancer cells. The new therapy could deal a double whammy against cancer, Shenderov says, by blocking B7-H3’s inhibition of the immune system’s recognition and killing of cancer cells, and also triggering a process called antibody-dependent cellular cytotoxicity (ADCC, for its acronym in English), which leads to the destruction of tumor cells through the activation of additional immune cells, such as macrophages and natural killer cells.
“Enoblituzumab seems safe and appears to activate the immune system in a way that involves both T cells and myeloid cells,” Shenderov says. “What this means is that if these results can be replicated in a larger randomized study, it raises the possibility that combining this therapy with local therapies with curative intent, such as surgical removal of the prostate or radiation therapy, could allow “That this drug potentially eliminates micrometastatic disease hiding elsewhere in the body and therefore preventing a significant number of men from experiencing recurrent disease. That could be a paradigm shift in prostate cancer.”
The median age of study participants was 64 years (age range 48-74). About half (47%) had a PSA greater than 10 ng/mL at diagnosis, which is abnormally high, and 50% had a Gleason score of group 5 on biopsy, meaning they had disease very aggressive. Patients were enrolled from February 2017 to June 2019. Enoblituzumab was confirmed to penetrate prostate tumors and bind to B7-H3 in the vast majority of participants, based on prostate samples studied after surgery.
Side effects of enoblituzumab were generally mild and included fatigue, neurological symptoms such as headache or dizziness, and flu- or cold-like symptoms. One patient developed inflammation of the heart (myocarditis), which resolved completely with steroid treatment and is a known side effect of other immune control medications.
Beyond safety and antitumor activity based on the drop in PSA to undetectable levels, the investigators also looked for changes in the tumor microenvironment before and after enoblituzumab treatment. They found an increase in cytotoxicity markers after treatment, consistent with the concept that the immune system was activated against the tumor cells. Tumors showed increased infiltration with granulocytes, leukocytes, and effector T cells, and there was approximately a doubling of cytotoxic T cell density after treatment.
“The findings are exciting but exploratory, and need to be confirmed in larger study cohorts,” said study senior author Emmanuel S. Antonarakis, MD, Clark Endowed Professor of Medicine and Director of GU Oncology for the Masonic Cancer Center. from the University of Minnesota. Antonarakis was the study’s principal investigator while 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 warrant the development of multifaceted approaches that include targeting of B7-H3 to optimize antitumor activity in prostate cancers and other solid malignancies,” he says.
The researchers are now planning a larger randomized trial of enoblituzumab in patients with newly diagnosed prostate cancer to assess the clinical activity of the drug compared to current standards of care.
Co-authors of this 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 article were MacroGenics Inc. of Rockville, Maryland (the manufacturer of enoblithuzumab); NanoString Technologies Inc. of Seattle; Seattle Adaptive Biotechnologies; Baltimore CDI Laboratories; Northwestern University Feinberg School of Medicine in Chicago; and Charles G. Drake, formerly at Johns Hopkins, who currently directs 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., maker of enoblituzumab. These relationships are managed by 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 he 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 its conflict of interest policies.