MSGID: 1:317/3 6434e26b   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    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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