Day: July 5, 2024

Giving patients with operable pancreatic cancers a three-pronged combination immunotherapy treatment consisting of the pancreatic cancer vaccine GVAX, the immune checkpoint therapy nivolumab and urelemab, an anti-CD137 agonist antibody treatment, is safe, it increases the amount of cancer-killing immune system T cells in the tumors and it appears effective when given two weeks prior to cancer-removal surgery, according to new research directed by Johns Hopkins investigators. A description of the work was published online June 20 in the journal Nature Communications. This study, led by researchers at the Johns Hopkins Kimmel Cancer Center, the Bloomberg~Kimmel Institute for Cancer Immunotherapy and the Johns Hopkins University School of Medicine, is the latest from an ongoing platform trial formed in 2015 to study immunotherapy treatments before surgery (neoadjuvant) and after surgery (adjuvant) for patients with pancreatic cancer. This format enables researchers to use data generated by the trial to advance development of immunotherapies for pancreatic cancer within the same study. In this most recent part of the trial, 10 participants received the combination treatment. The median disease-free survival — the amount of time after treatment during which no cancer is found — was 33.51 months, and the median overall survival — time to death — was 35.5 months. These were higher than found in previous arms of the trial that tested the pancreatic cancer vaccine alone and in combination with nivolumab, but because of the small number of patients, the results did not have statistical significance. The tumor specimens studied in the recent arm also had much higher amounts of cancer-killing immune cells than specimens from patients given only the vaccine or the vaccine plus nivolumab. The results suggest that this therapy combination warrants further study in a larger clinical trial, says senior study author Lei Zheng, M.D., Ph.D., co-director of the Pancreatic Cancer Precision Medicine Center of Excellence and professor of oncology at the Johns Hopkins University School of Medicine. The platform trial has two purposes regarding pancreatic cancer treatments given during the two-week “window of opportunity” prior to surgery, Zheng says. First, it allows the immunotherapies to teach the patient’s immune cells how to respond to tumors, so they can continue surveillance later if the cancer recurs. Second, it enables investigators to see, by evaluating the tumors removed during surgery, how well the tumors respond to the treatment. A fourth arm of the trial, studying anti-interleukin-8 neutrophil-blocking antibodies in pancreatic tumors, is ongoing. Zheng is available for comment. To schedule an interview, contact Valerie Mehl at [email protected] or Amy Mone at [email protected]. Journal Nature Communications Article Publication Date 20-Jun-2023 Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

The core foundation of precision medicine, and in turn, precision oncology, is a personalized approach to treatment that focuses on targeting specific molecular features that impact how cancer cells proliferate and spread. Targeted therapies, often exploiting specific proteins present on the surface of cancer cells, provide additional avenues for patients whose tumors express these targets, leading to more favorable outcomes than standard therapy alone. In prostate cancer, “PSMA [prostate specific membrane antigen] is the most comprehensively validated cell surface target,” said Dr. Erolcan Sayar, a postdoctoral research fellow in the Haffner Lab, part of Fred Hutch’s Human Biology Division. In recent years, great strides have been made in targeting PSMA for treatment, with radioligand therapy 177Lu-PSMA-617 receiving FDA approval for treating patients with advanced prostate cancer. “However, the expression levels of PSMA can vary among different tumors and even within the same tumor. The impact of heterogeneous PSMA expression on treatment options is primarily related to the use of PSMA-targeted therapies. These therapies, such as PSMA-targeted radionuclide therapy (e.g., 177Lu-PSMA-617), rely on the presence of PSMA on the surface of cancer cells for their effectiveness. Prior clinical trials have suggested that patients with low or heterogenous PSMA expression show reduced therapeutic benefit from PSMA-directed therapies,” explained Dr. Sayar. Based on this, Dr. Sayar, under the mentorship of Dr. Michael Haffner, led a study recently published in JCI insight, to better understand the heterogeneous expression patterns and molecular underpinnings of PSMA, with the goal of improving treatment options for patients with metastatic castration resistant prostate cancer (mCRPC), a lethal disease state. For their study, the authors extensively profiled samples derived from patients with mCRPC and determined variable broad expression patterns across different subtypes of the disease. For example, tumors that rely on the androgen receptor for proliferation exhibited diverse PSMA expression patterns, while neuroendocrine tumors had generally lower expression of PSMA at both the mRNA and protein level. Next, to assess both inter- and intra-tumoral heterogeneity, the authors profiled samples derived from multiple distinct metastatic sites within the same patient with mCRPC. “A major advantage of our tissue donation based study is the ability to study multiple metastatic sites in a given patient. This setting allows for the detailed evaluation of inter- and intra-tumoral heterogeneity. We are grateful to the patients and their families for their contributions to the UW Medical Center Prostate Cancer Tissue Donation Program,” expressed Dr. Sayar. They observed substantial intertumoral (between different metastatic sites) heterogenous PSMA expression, in addition to heterogeneous expression of PSMA present intratumorally (between different spatial sites within one metastatic lesion).

Shahneen Sandhu, PhD, MBBS, FRACP Early findings from the phase 1 LuPARP study (NCT03874884) demonstrated that patients with metastatic castration-resistant prostate cancer (mCRPC) experienced enhanced antitumor activity following treatment with the PARP inhibitor olaparib (Lynparza) in addition to the radioligand lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617).1 Among 32 patients treated across dose levels, the prostate-specific antigen (PSA) response rate of at least 50% was observed in 66% of patients, with 14 of the 32 patients (44%) achieving a PSA response of at least 90%. The overall response rate was 78%. Further, safety findings showed that no dose-limiting toxicities were reported across dose levels.1 “I think this is intriguing data, although early, but may be suggestive of a deepening of responses from the combination therapy,” Shahneen Sandhu, PhD, MBBS, FRACP, said in a presentation of the data during the 2023 ASCO Annual Meeting. “And the reason that’s important is we do know, based on other data sets, that a PSA response of 90% does in fact, translate into improved progression-free survival [PFS].” “Lutetium-PSMA-617 is a radioligand therapy that is directed to prostate-specific membrane antigen [PSMA] and has previously been shown to improve both PFS and overall survival [OS],” Sandhu, who is an associate professor in the Department of Medical Oncology and a consultant medical oncologist and researcher in the melanoma and uro-oncology units at the Peter MacCallum Cancer Center in Melbourne, Australia said. “Olaparib is a potent PARP inhibitor that has also been shown to improve PFS and OS in men with mCRPC with an underlying DNA repair defect or homologous recombination repair defect. Both Lutetium-PSMA-617 and olaparib are very well-tolerated and are widely used. Lutetium-PSMA-617 delivers a payload of beta radiation to PSMA-expressing tumors. Lutetium-PSMA-617 predominantly causes single strand DNA breaks. And these DNA breaks are repaired by PARP-dependent base excision repair. Therefore, blocking PARP could result in conversion of DNA single strand breaks to more lethal double strand breaks [via] fork collapse.” Forty-eight patients with prostate-specific membrane antigen (PSMA) avidity were enrolled to LuPARP. This was defined as those with a minimum uptake of SUVmax of 15 at a site of disease, and SUVmax greater than 10 at other sites of disease measuring at least 10 mm identified using 68Ga/18F-PSMA PET/CT.2 Patients received olaparib 50 to 300 mg orally in a 3 + 3 dose escalation lutetium Lu 177 vipivotide tetraxetan was administered every 6 weeks for 6 cycles at 7.4 GBq. Biomarker collection and imaging occurred as follows: PSMA PET/CT at baseline and every 12 weeks for 48 weeks, then every 24 weeks; FDG PET at baseline; bone scan and CT-CAP at baseline then every 12 weeks; blood and biomarker analysis for PBMC, circulating tumor cells, circulating tumor DNA, serum levels were done very 12 weeks and at disease progression; tumor biopsies were obtained for archival storage at base line, between weeks 2 to 4, and at disease progression.1 Nine cohorts were included in the dose-escalation design. Patients in cohort 1 (n = 3) received olaparib at 50 mg, at 100 mg in cohort 2 (n = 3), at 150 mg in cohort 3 (n = 3), at 200 mg in cohort 4 (n = 3), at 250 mg in cohort 5 (n = 4), and at 300 mg in cohort 6 (n = 3). Each of these cohorts had olaparib administered on days 2 through 15. Those in cohort 7 (n = 4) received olaparib at 200 mg and those in cohort 8 received the agent at 300 mg on days –4 through 14. Finally, those in cohort 9 (n = 6) received olaparib at 300 mg on days –4 through 18. The median number of treatment cycles across populations was 5 (range, 2-6). Specifically for cohorts 1-9 the median cycles of treatment were 4 (range, 4-5); 6 (range, 5-6); 6 (range, 2-6); 3 (range, 2-4); 6 (range, 4-6); 6 (range, 5-6); 5.5 (range, 3-6); 4 (range, 3-6); and 3 (range, 2-5).1 Overall, most adverse events (AEs) were grade 1 or 2. Grade 1 events included anemia (n = 5), neutropenia (n = 1), thrombocytopenia (n = 5), nausea (n = 13), dry mouth (n = 22), constipation (n = 7), vomiting (n = 3), gastroesophageal reflux (n = 2), diarrhea (n = 3), weight loss (n = 1), anorexia (n = 6), dry eye (n = 2), and fatigue (n = 15). Grade 2 events were anemia (n = 3), thrombocytopenia (n = 2), nausea (n = 6), dry mouth (n = 3), constipation (n = 2), vomiting (n = 1), gastroesophageal reflux (n = 1), and weight loss (n = 1).1 Grade 3 events occurred in cohorts 5 and 6 at the 250-mg and 300-mg dose levels for olaparib, respectively. In cohort 5, these events 1 each of anemia, thrombocytopenia, and neutropenia, which was deemed a serious treatment-related AE and classified as febrile neutropenia. In cohort 6, the grade 3 events were 1 instance each of anemia and neutropenia. No grade 4 events were reported.1 Dose reductions because of treatment-related AEs occurred in 9% of patients overall, including 1 patient each from cohorts 3, 5, and 6. Two dose delays were reported 1 each in cohorts 3 and 6. Sixteen patients will be enrolled to the dose-expansion phase to receive the recommended dose of olaparib: 300 mg orally on days –4 to 18 of each 6-week cycle. The primary end points are dose-limiting toxicities (DLTs) and recommended phase 2 dose. The secondary end points are safety and antitumor activity including radiographic PFS, PSA response rate, PSA PFS, overall response rate, and OS. Following completion of therapy, patients are required to attend an end of treatment visit and will be followed for PFS and OS outcomes.1 Of note at the time of data cutoff, patients enrolled in cohorts 8 and 9 were in early treatment cycles. The median age was 71 years (range 52-84) with 56% of patients having an ECOG performance status of 0 and the remaining 44% having a status of