PCF held its 26th Annual Scientific Retreat in October. In attendance were 665 participants from 188 institutions, 18 countries, and 5 continents – the largest turnout in PCF history! Scientific Retreat is an opportunity for PCF-funded investigators and other experts in the field of prostate cancer research to learn from each other through presentations and informal networking.
From 42 total panels and presentations, PCF’s Director of Research Dr. Andrea Miyahira has curated the Top 5 New Discoveries for Patients. (Each story includes a “What This Means for Patients” summary.)
1. Testosterone Effects on Innate Immunity: Implications for Combination Therapies
Bipolar androgen therapy (BAT) is an experimental treatment approach in which men are rapidly cycled between extremely high and extremely low (castrate) levels of testosterone (T). This is hypothesized to allow killing of both androgen receptor (AR)-expressing cells (vulnerable at extremely high T levels) and AR-low cells (vulnerable at castrate T levels). Dr. Samuel Denmeade and Dr. Sushant Kachhap of Johns Hopkins University presented promising results from BAT therapy clinical trials, which demonstrated that BAT therapy can resensitize men with mCRPC to enzalutamide, and improve PSA progression-free survival.
Interestingly, Exceptional Responses have been observed in some patients who were treated with checkpoint immunotherapy after BAT therapy. These results have led to a clinical trial testing BAT therapy in combination with vs. followed by nivolumab. The mechanisms which cause this sensitivity are being explored. Preliminary studies indicate that extremely high T levels activate the STING pathway, which activates immune responses and tumor infiltration by tumor-killing Natural Killer (NK) cells.
What this means to patients: Drs. Denmeade and Kachhap have made the startling observation that some patients treated with BAT therapy and progress, go on to have Exceptional Responses when treated subsequently with checkpoint immunotherapy. This treatment approach is now being formally tested in clinical trials and the mechanisms which drive this are being studied.
2. Real World Validation of Deep Learning Algorithms in the Assessment of Metastasis by Medical Imaging of Veterans with Prostate Cancer
PSMA-PET imaging is a new imaging modality that is highly sensitive and specific for prostate
cancer, and outperforms conventional imaging methods such as CT, bone scans, and MRI.
Dr. Matthew Rettig and Dr. Nicholas Nickols of University of California, Los Angeles and the VA Greater Los Angeles Healthcare System presented results from a study that compared PSMA-PET vs conventional imaging (99mTc-MDP or NaF PET bone scan, CT or MRI of abdomen/pelvis) for diagnosis and management of 92 Veterans with high-risk prostate cancer at initial staging.
PSMA-PET imaging findings identified an altered risk group/stage that resulted in a major change in treatment recommendations in 35% of patients. Artificial intelligence (AI) algorithms are also being developed to evaluate PSMA-PET imaging. An AI algorithm using intraprostatic PSMA-PET imaging alone in veterans with prostate cancer was found to be highly predictive of co-existing metastatic disease. PSMA-PET AI prediction was superior to clinical predictors alone (clinical T stage, biopsy Gleason, % positive cores, PSA), and was not improved by the addition of clinical predictors.
What this means to patients: PSMA-PET imaging is a practice-changing imaging technology for prostate cancer that is highly sensitive and will likely soon be FDA-approved. These studies demonstrate significant clinical impact of PSMA-PET, including directing treatment recommendations, and having the ability to predict metastatic disease from prostate-only imaging.
3. CD46 as a Novel Target in Metastatic Castration Resistant Prostate Cancer
CD46 is a protein that helps cancer cells to evade killing by immune cells, and is highly upregulated in castrate resistant prostate cancer (CRPC) but not normal cells. CD46 expression may be particularly high in cases of neuroendocrine prostate cancer. Thus, CD46 represents a promising target for prostate cancer immunotherapy. Drs. Rahul Aggarwal, Eric Small, Bin Liu, and Larry Fong, and the prostate cancer team at the University of California, San Francisco have developed a CD46-targeting treatment (CD46-ADC), with potent anti-tumor activity in preclinical prostate cancer studies. Early studies suggest CD46-ADC may be synergistic with checkpoint immunotherapy and androgen receptor (AR)-targeted therapy.
The team has recently initiated a first-in-human Phase I clinical trial to test the efficacy and safety of CD46-ADC in patients with metastatic CRPC. Based on results from this study, the team may pursue trials testing CD46-ADC in combination with checkpoint immunotherapy and AR-targeted therapy. Dr. Rob Flavell, a nuclear medicine physician scientist at UCSF, is also developing a novel PET radio tracer targeting CD46 that may be used as a companion biomarker and theranostic agent to image CD46 expression. Studies in mice are promising thus far.
What this means to patients: Dr. Aggarwal and the UCSF team have identified CD46 as a promising new therapeutic target in prostate cancer, that may also have synergy with checkpoint immunotherapy and AR-targeted therapy. The team have developed a novel CD46-
targeting agent, have completed preclinical development and have recently initiated a first-in-man Phase I trial.
4. Immunotherapy-Associated Cardiotoxicities: Of Mice and Men
Immune checkpoint inhibitors (ICI) are highly effective treatment options that can produce long-term remissions and even cures in some patients with cancer, although this treatment type is still being optimized for prostate cancer. Dr. Javid Moslehi of Vanderbilt University Medical Center has found that about 1% of cancer patients treated with combination checkpoint immunotherapy develop myocarditis, with a 50% mortality rate in affected patients. This new clinical syndrome has been termed “Immune Checkpoint-Inhibitor (ICI) Associated Myocarditis.” This syndrome occurs early, is unpredictable, and is defined by T cell and macrophage infiltration into heart tissue, leading to various heart problems, including arrhythmias. The main risk factor for ICI-myocarditis is ICI-combination treatment (for example, CTLA4 + PD1 inhibition).
Dr. Moslehi’s laboratory has created pharmacological mouse models of ICI-myocarditis. In collaboration with Dr. James Allison’s group, he has additionally made genetic knockout models. In both mouse models, CTLA4 signaling appears to be critical for the development of myocarditis. Early data from both mouse models and patients with ICI-myocarditis suggest that treatment with the CTLA4-ligand abatacept could ameliorate the phenotype and even prevent mortality. Dr. Moslehi’s group is now utilizing a web-based platform (www.cardioonc.org) which he has used to collect ICI-myocarditis cases to start an international trial with abatacept for ICI-myocarditis treatment.
What this means to patients: Dr. Moslehi identified a new syndrome of “Immune Checkpoint Inhibitor (ICI)- Associated Myocarditis” that affects about 1% of cancer patients treated with combination checkpoint immunotherapy and has a 50% mortality rate. Treatment with the CTLA4-ligand abatacept may prevent myocarditis in these patients. Investigations into novel treatment-associated syndromes and therapeutic approaches to overcome these morbidities and mortalities is critical for advancing cancer patient care.
5. The Biology and Therapeutic Impact of Targeting IL-23 in Prostate Cancer
Myeloid-derived suppressor cells (MDSCs) are a class of immune cells that infiltrate tumors in
large numbers and promote cancer growth. Their role in driving prostate cancer and as treatment targets is an important area in need of study. Dr. Andrea Alimonti and his team at the Institute of Oncology Research, Switzerland found that MDSCs are significantly increased in mouse models of castrate-resistant prostate cancer (CRPC) and promote the development of resistance to androgen deprivation therapy (ADT) via secretion of IL-23. ADT, part of the standard of care for advanced prostate cancer, stops testosterone from being produced or directly blocks it from acting on prostate cancer cells. Treatment of these models with an anti-IL-23 antibody enhanced the efficacy of ADT.
IL-23 and MDSCs were also increased in metastatic CRPC tumors compared with hormone-sensitive prostate cancer. Based on these findings, in collaboration with the team of Dr. Johann de Bono of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust (UK), a Phase I/II clinical trial is being initiated in mCRPC patients assessing the safety and efficacy of IL-23a (a powerful anti-psoriasis drug) combined with ADT.
What this means to patients: New treatment strategies are urgently needed for mCRPC. Dr. Alimonti and team have identified MDSCs and IL-23 as novel drivers and therapeutic targets in CRPC and will initiate a clinical trial to test an IL-23-targeting therapy for the treatment of CRPC. This drug is used for psoriasis, and represents a novel drug repurposing approach.