The Cancer Research Institute (CRI) and Parker Institute for Cancer Immunotherapy (PICI) will unveil details of their newest clinical collaboration, PORTER, during a poster session on Friday, November 8, at the upcoming annual meeting of the Society for Immunotherapy of Cancer (SITC2019), which takes place November 6-10, 2019, in National Harbor, Maryland, USA.
Vanessa M. Lucey, Ph.D., MBA, director of the CRI Clinical Accelerator and Venture Fund, and Theresa LaVallee, Ph.D., PICI’s vice president of translational medicine and regulatory affairs will present details of PORTER’s unique multi-arm, multi-center platform design testing combinations of treatments including immunotherapy for patients with metastatic, castration-resistant prostate cancer. Joining them will be poster co-authors Nina Bhardwaj, M.D., Ph.D., and Matthew Galsky, M.D., both of the Icahn School of Medicine at Mount Sinai in New York City. The trial is being led by Lawrence Fong, M.D., of the University of California, San Francisco, and PICI’s Leonardo Nissola, M.D., is the poster’s first author.
Patients with metastatic castration-resistant prostate cancer typically do not respond to immunotherapy when given alone as a monotherapy. Data from clinical studies of immunotherapy combinations in other hard-to-treat cancers suggest that combination approaches may prove a more effective treatment strategy for these patients. PORTER will initially test a variety of therapy combinations in three different trial arms.
“The first approach,” according to Sumit Subudhi, M.D., Ph.D., a lead investigator of this trial at the University of Texas MD Anderson Cancer Center, “includes a treatment called NKTR-214 that activates IL-2 receptor signaling, which increases the number of effector T cells and Natural Killer cells that infiltrate the tumor—two important types of immune cells in fighting cancer. Furthermore, the drug does not activate regulatory T cells that can suppress immune activity.” In combination with NKTR-214, this first group of patients will also receive nivolumab, which targets the PD-1 immune checkpoint to prevent the desired T cell response from prematurely shutting down.
“The second combination is pretty interesting and novel because it’s targeting a pathway called Flt3 in order to get immune cells called dendritic cells more active and make them engage and activate the T cells. This strategy also involves radiation, which causes cancer cells to die in a way that attracts the immune system. These dying cancer cells release their neoantigens, which should activate the dendritic cells, which in turn should mobilize and activate the T cells. Then when these activated T cells increase PD-1 expression, the PD-1-blocking nivolumab that is also added to this combination overcomes that adaptive resistance mechanism.”
“The third approach,” Subudhi added, “includes a DNA vaccine targeting PSA and PSMA (prostate-specific maturation antigen), two proteins that are highly expressed in prostate cancer. T cells in our body, however, don’t tend to kill the cancers that express them, because these are normal proteins that are expressed at an abnormal level.” Coupling the vaccine with drugs targeting the Flt3 and PD-1 pathways should help the T cells kill off the prostate cancer cells.
Bringing these various therapeutic agents together in the PORTER trial is possible thanks to a unique collaboration between CRI, PICI, and several industry partners: Bristol-Myers Squibb, Celldex Therapeutics, Inovio Pharmaceuticals, and Oncovir, Inc. Additionally, the trial’s platform design provides flexibility for the future, so that as new discoveries are made, new treatment combinations can be incorporated into the study more quickly and cost-effectively. This ultimately enables compelling, scientifically-based strategies to be delivered to patients in the clinic more rapidly.
The idea for the PORTER trial originated in October 2017, when CRI and PICI met with experts to discuss the most pressing issues in prostate cancer. Overall, the group felt that a trial in metastatic castration-resistant prostate cancer, funded and supported by a nonprofit, would make the greatest impact. Since that time, CRI and PICI have convened prostate and IO experts in quarterly meetings to discuss future combinations for this platform study.
In addition to the unveiling of the PORTER study, which has already begun to enroll patients, the following CRI scientists will be giving talks on a variety of immunotherapy topics, in addition to dozens more who will be presenting posters:
- John C. Bell, Ph.D., of the University of Ottawa, CRI CLIP Investigator (2016-2018)
- Nina Bhardwaj, M.D., Ph.D., of the Icahn School of Medicine at Mount Sinai, CRI Scientific Advisory Council member and recipient of multiple CRI grants (starting in 1985)
- Joshua Brody, M.D., of the Icahn School of Medicine at Mount Sinai, CRI CLIP Investigator (2015-2017)
- Raphael Clynes, M.D., Ph.D., of Xencor, Inc., CRI Investigator Award recipient (2000-2004)
- Michael A. Curran, Ph.D., of The University of Texas MD Anderson Cancer Center, CRI CLIP Investigator (2016-2018)
- Charles G. Drake, M.D., Ph.D., of Columbia University Medical Center, CRI Scientific Advisory Council member
- Michael Dustin, Ph.D., The Kennedy Institute of Rheumatology at the University of Oxford, CRI Scientific Advisory Council member
- Sacha Gnjatic, Ph.D., of the Icahn School of Medicine at Mount Sinai, CRI Clinical Grantee (2001-2017)
- Patrick Hwu, M.D., of University of Texas M.D. Anderson Cancer Center, CRI Scientific Advisory Council member
- Carl H. June, M.D., of the University of Pennsylvania, CRI Clinical Grantee (2013-2016)
- Matthew Krummel, Ph.D., of the University of California, San Francisco (UCSF), CRI Investigator Award recipient (2004-2008)
- Thomas Urban Marron, M.D., Ph.D., The Mount Sinai Hospital, CRI CLIP Investigator (current)
- Anjana Rao, Ph.D., of the La Jolla Institute for Immunology, CRI Scientific Advisory Council member and recipient of multiple CRI grants (starting in 1981)
- David Raulet, Ph.D., of the University of California, Berkeley, CRI Investigator Award recipient (1986-1990)
- Craig L. Slingluff, M.D., of the University of Virginia, CRI Scientific Advisory Council member and recipient of multiple CRI grants (starting in 1996)
- Stefani Spranger, Ph.D., of the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT), CRI postdoctoral fellow (2014-2016)
- Suzanne L. Topalian, M.D., of the Johns Hopkins University School of Medicine, member of the CRI-SU2C “Dream Team” (2013-2017)
- Dmitry Zamarin, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center, CRI Clinical Accelerator Investigator (current)
- Hassane M. Zarour, M.D., of the University of Pittsburgh, and recipient of multiple CRI grants (starting in 1997)