City of Hope researchers to present exciting new treatments at ASCO 2023

Research on a heart medication for childhood cancer survivors and new immunotherapies for blood and solid tumors will be presented at annual oncology conference

City of Hope physicians will present research on promising treatments for blood, prostate and other cancers, as well as studies on genetic testing for hereditary cancers and on reducing heart disease in childhood cancer survivors, at the 2023 American Society of Clinical Oncology's (ASCO) annual conference from June 2 to 6 in Chicago.

More than 40,000 oncology professionals and others will attend the conference, or join virtually, to learn about the latest scientific research on cancer treatment, detection and prevention.

"This year's ASCO Annual Meeting highlights the exceptional work City of Hope doctors and scientists are leading with the hope of finding better treatments against a wide range of cancers," said Steven T. Rosen, M.D., City of Hope provost and chief scientific officer, Irell & Manella Cancer Center Director's Distinguished Chair. "Whether it's working on our own immunotherapy trials for solid tumors or partnering with companies to find novel medicines, City of Hope is committed to transforming cancer care for our patients and beyond."

City of Hope doctors and scientists will present oral and poster presentations on the following and other abstracts.

Blood pressure medication shows promise in lowering heart failure risk for childhood cancer survivors

For people who were treated with anthracyclines - a class of chemotherapy drugs - for childhood cancers, heart failure can be a devastating side effect that develops later in life. To date, there have been no effective therapies to prevent heart failure in long-term childhood cancer survivors who have been treated with anthracyclines.

Now, Saro Armenian, D.O., M.P.H., City of Hope's Barron Hilton Chair in Pediatrics, The Norman and Sadie Lee Foundation Professor in Pediatrics and director of the Division of Outcomes Research/Intervention, has led a Phase 2b clinical trial examining the effectiveness of a low-dose blood pressure medication called carvedilol to improve heart health in these survivors.

Saro Armenian, D.O., M.P.H.

The double-blinded trial was conducted at 30 sites and enrolled 182 participants to either receive low-dose carvedilol (12.5 mg/day) or a placebo.

Armenian and his team found that carvedilol was shown to be safe and effective in reversing early signs of heart injury during the two-year study period. Compared to the placebo arm, participants who took carvedilol had significantly better measurements of heart health at two years.

"There are an estimated 500,000 long-term survivors of childhood cancer in the U.S. alone, and more than 40% will have been treated with anthracycline-based chemotherapies," said Armenian, who will give an oral presentation of the trial's outcomes on Monday, June 5, at 9:12 a.m. CDT. "Our study is one of the first to demonstrate the safety and efficacy of a readily available heart failure prevention strategy in long-term survivors, setting the stage for optimizing cardiovascular outcomes in this growing population of survivors who will live for decades after their initial diagnosis."

New treatment for relapsed or refractory leukemias performs well in first clinical trial

For patients with blood cancers that have returned or are treatment-resistant, the existing therapy options are few.

In an effort to expand treatment choices, Anthony S. Stein, M.D., associate director of City of Hope's Gehr Family Center for Leukemia Research and professor with the Division of Leukemia, Department of Hematology & Hematopoietic Cell Transplantation, and researchers from other leading academic institutions around the world are testing a new approach. Early results from the first-in-human study of SAR443579 (SAR'579) in relapsed or refractory acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia or high-risk myelodysplasia have revealed positive results.

Anthony S. Stein, M.D.

When activated, natural killer (NK) cells have innate cell killing function. SAR'579 is a trifunctional anti-CD123 NK cell engager that targets NK cells through CD16 and NKp46 and the tumor antigen CD123 on the AML cell. This co-engagement of the NK cells leads to an optimal activation, resulting in tumor cell death.

In an oral presentation titled, "A first-in-human study of CD123 NK cell engager SAR443579 in relapsed or refractory acute myeloid leukemia, B-cell acute lymphoblastic leukemia, or high-risk myelodysplasia," being presented on Friday, June 2, at 2:24 p.m. CDT, Stein will outline findings from 23 AML patients in a Phase 1/2 clinical trial who received SAR'579, under development by Sanofi, to evaluate the treatment for safety, efficacy and anti-leukemic activity. Patients received a median of two cycles for a median duration of seven weeks with escalating doses. The most common side effects were infusion-related reactions and nausea.

"We found that SAR'579 was well-tolerated in heavily pretreated patients with refractory AML," Stein said. "In addition, we observed clinical benefits in the patients. Thirteen percent of all patients achieved a complete remission, and 37.5% achieved a complete remission at the maximum highest dose of 1,000 micrograms per kilogram, once a week. These are encouraging findings for patients with AML."

The clinical trial continues to accrue patients globally. Stein and researchers from other leading academic institutions are working to define the SAR'579's optimal dose with the best safety and highest response profile.

Benefits of brexu-cel treatment for relapsed or refractory mantle cell lymphoma hold up in large, real-world study

Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T cell therapy and a Kite product. CAR T cell therapies use the body's own cells, known as T cells, from the immune system to fight cancer.

Brexu-cel was first approved by the U.S. Food and Drug Administration in 2020 for relapsed or refractory (R/R) mantle cell lymphoma (MCL). Accelerated approval was granted based on a single-arm Phase 2 clinical trial called ZUMA-2. Now, an analysis led by Swetha Kambhampati, M.D., City of Hope assistant professor in the Division of Lymphoma, has shown the treatment works well outside of the clinical trial setting.

Swetha Kambhampati, M.D.

Kambhampati and a team of researchers evaluated follow-up, updated data from 380 patients who participated in the ZUMA-2 trial and were also registered in the Center for International Blood and Marrow Transplant Research observational database. They found that at a median follow-up of 12 months, the objective response rate, or cancer diminishing, was 90%, and the complete response rate, which refers to the disappearance of all signs of cancer, was 78%, with a median duration of response of 21.7 months. These results were comparable to those seen in the ZUMA-2 trial.

The team found that complete response rates were higher in patients who received brexu-cel in earlier lines of therapy, suggesting that treating R/R MCL patients with brexu-cel sooner may be beneficial. Kambhampati and others also examined outcomes based on prior treatment types and found them to be largely consistent in MCL patients who had received bruton tyrosine kinase inhibitors, a therapy that stops B cell growth to treat lymphoma, bendamustine (a type of chemotherapy), or autologous stem cell transplant therapy before taking brexu-cel.

"Our results show that brexu-cel has demonstrated efficacy and safety in the real-world setting in R/R MCL, regardless of prior therapy, and it has improved efficacy when used in the earlier lines of therapy," said Kambhampati, who will give an oral presentation on the study on Tuesday, June 6, at 11:57 a.m. CDT. "But it will be important to evaluate the durability of responses with brexu-cel in R/R MCL further with longer follow-up."

CAR T cell therapy tested in the treatment of metastatic castration-resistant prostate cancer patients

Chimeric antigen receptor (CAR)-engineered T cell therapies represent a recent and huge advance in cancer care for blood cancers and some brain tumors. Researchers are now looking to apply the approach to more solid tumors, which represent roughly 90% of all adult cancers.

Saul Priceman, Ph.D.

CAR T cell therapies work by boosting the body's own immune system to fight disease. Saul Priceman, Ph.D., associate professor in City of Hope's Department of Hematology & Hematopoietic Cell Transplantation and associate director of Translational Sciences & Technologies in the T Cell Therapeutics Research Laboratory, and Tanya Dorff, M.D., City of Hope's section chief, Genitourinary Disease Program, have been working to develop CAR T cell therapy for advanced prostate cancer.

Dorff will share results from a Phase 1 clinical trial using CAR T in metastatic, prostate stem cell antigen (PSCA)-positive, castration-resistant prostate cancer patients during a poster discussion on Saturday, June 3, starting at 1:15 p.m. CDT. (Metastatic refers to a cancer that has spread and castration-resistant refers to prostate cancer that keeps growing despite little to no testosterone, which is what usually causes prostate cancer to grow.)

Using a CAR T cell developed at City of Hope, Priceman, Dorff and a team of researchers recruited 14 patients with PSCA-positive prostate cancer. PSCA is highly expressed in most prostate cancers, and targeting PSCA with CAR T cell therapy has been previously shown to be potentially effective and feasible.

Tanya Dorff, M.D.

The team found that the PSCA-CAR T cell therapy had anti-cancer effects in these patients, more so in patients who had also received lymphodepletion (LD) chemotherapy. They also found that a lower dose of LD chemotherapy lessened the toxicity, or harmful effects, of the treatment without clear negative impact on CAR T expansion.

"More work needs to be done to optimize the use of CAR T cell therapy in prostate cancer since we are seeing occasional very deep responses, but not as many of them, or with as much durability, as we would like," Dorff said. "But we remain enthusiastic about the potential of this treatment. This study has pushed cellular immunotherapy one step closer to being a treatment option for advanced prostate cancer."

To further test the approach, the team will open a Phase 1b clinical trial with a new dosing strategy soon, which they believe will achieve greater efficacy with lower toxicity.

Universal testing could help identify people with hereditary cancer syndromes

Many people with hereditary breast-ovarian cancer syndrome (HBOC) and Lynch syndrome - caused by mutations in the genes, such as BRCA1, BRCA2, ATM, PALB2, and Lynch syndrome-associated genes - are unaware of their risk of developing cancer. While screening efforts catch about half of the people carrying these mutations, a better approach is needed.

Stephen Gruber, M.D., Ph.D., M.P.H.

City of Hope's Implementing Next-generation Sequencing for Precision Intervention and Risk Evaluation (INSPIRE) study, led by Stephen Gruber, M.D., Ph.D., M.P.H., the Eva and Ming Hsieh Family Director's Chair of the Center for Precision Medicine; Stanley Hamilton, M.D., professor and chair of the Department of Pathology; and Stacy W. Gray, M.D., professor and chief of the Division of Clinical Cancer Genomics and deputy director of the Center for Precision Medicine, hopes to be just that. The research project makes germline genetic testing available without charge to every participating City of Hope patient.

"Every mutation that is known to be associated with elevated cancer risk is actionable at some level," said Gray, who will be presenting data at ASCO from the INSPIRE study. "It could mean increased screenings to catch cancer at its earliest, most treatable stages, or risk-reducing surgery, or new medications."

Stacy Gray, M.D.

In a poster session on Saturday, June 3, from 1:15 to 4:15 p.m. CDT, Gray will outline recent findings from an informatics study aimed at determining whether genetic testing, through outreach like INSPIRE, leads to increased intervention for people carrying the BRCA mutation. By querying codified data, which refers to grouping data in meaningful categories, in City of Hope's electronic data warehouse before and after germline testing, Gray and her study collaborators found that out of 217 patients whose testing revealed a known or likely BRCA mutation, 83% had procedures, imaging and/or therapy potentially related to the BRCA mutation.

"This suggests that universal genetic testing identifies patients who have inherited cancer risk who previously did not know their risk. Moreover, our study will evaluate whether individuals with BRCA and

Stanley Hamilton, M.D.

other actionable germline findings receive higher levels of relevant health care," Gray said. "However, this initial informatics approach is limited because key information on prior germline testing and motivations for surgery, such as whether a patient received a mastectomy as part of a treatment plan or chose one as a preventive measure, are not adequately captured in codified data."

She says that codified electronic health record queries will need to be augmented by text mining and/or manual chart review to fully capture care and assess the clinical utility of system-wide genetic care delivery interventions.

Given the promising findings of this initial work, Gray and the team are now evaluating care for the more than 17,000 patients who have enrolled in the INSPIRE study.