PROSTATE CANCER

Neoadjuvant enoblituzumab in localized prostate cancer: A single-arm, phase 2 trial

Findings from a recent Phase II study suggest that enoblituzumab-a new monoclonal antibody-is a safe option for patients with aggressive prostate cancer and may induce clinical activity against cancer throughout the body (Nat Med 2023; doi:10.1038/s41591-023-02284-w). Enoblituzumab binds to B7-H3, a protein that is overexpressed on prostate cancer cells and believed to interfere with the immune system's ability to attack cancer cells. The clinical trial included 32 patients with high-risk or very high-risk prostate cancers who were scheduled for surgery. They were treated with six weekly infusions of enoblituzumab prior to surgery and were then followed for an average of 30 months.

Primary outcomes were safety and undetectable prostate-specific antigen (PSA) level (PSA0) 1 year postprostatectomy. Patient characteristics were as follows: median age of 64 (age range: 48-74), 47 percent had a PSA greater than 10 ng/mL at diagnosis, and 50 percent had Gleason Grade Group 5 at biopsy. Patients were enrolled from February 2017 through June 2019. Twenty-one patients (66%) had an undetectable PSA level 12 months following surgery, according to the study authors, who noted that this suggests there was no sign of residual disease. In terms of safety, the drug was well-tolerated overall with no patients having any surgical delays or medical complications during or after the operation. The study authors reported that 12 percent of patients experienced Grade 3 adverse events and no Grade 4 events occurred.

"The use of B7-H3-targeted immunotherapy in prostate cancer is feasible and generally safe, and preliminary data suggest potential clinical activity," the investigators wrote. "The present study validates B7-H3 as a rational target for therapy development in prostate cancer with larger studies planned."

AUTHOR COMMENTARY: "Enoblituzumab appears safe and seems to activate the immune system in a way that involves both T cells and myeloid cells," according to study author Eugene Shenderov, MD, PhD, Assistant Professor of Oncology at Johns Hopkins University School of Medicine. "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."

CHILDHOOD CANCER

Specific causes of excess late mortality and association with modifiable risk factors among survivors of childhood cancer: A report from the Childhood Cancer Survivor Study cohort

Researchers found childhood cancer survivors have higher mortality than the public; however, survivors with a healthy lifestyle and fewer heart disease risk factors had lower risk, according to a report from the Childhood Cancer Survivor Study (Lancet 2023; doi:10.1016/S0140-6736(22)02471-0). This multi-institutional, hospital-based, retrospective cohort study evaluated late mortality (death >=5 years from diagnosis) and specific causes of death in 34,230 5-year survivors of childhood cancer who were diagnosed at younger than 21 years old from 1970 to 1999. Median follow-up from time of diagnosis was 29 years.

Researchers specifically evaluated the following factors: demographic, self-reported modifiable lifestyle (i.e., smoking, alcohol, physical activity, and BMI), and cardiovascular risk factors (i.e., hypertension, diabetes, and dyslipidemia) associated with health-related mortality. This excludes death from primary cancer and external causes and includes death from late effects of cancer therapy, according to the researchers.

The data showed that 40-year cumulative all-cause mortality was 23.3 percent, with 3,061 of 5,916 deaths from health-related causes. Additionally, the researchers found that survivors who were 40 years or more from diagnosis experienced 131 excess health-related deaths per 10,000 person-years, including those due to the top three causes of health-related death in the general population: cancer, heart disease, and cerebrovascular disease. According to the findings, healthy lifestyle as well as the absence of hypertension and diabetes were each associated with a 20-30 percent reduction in health-related mortality independent of other factors.

"Survivors of childhood cancer are at excess risk of late mortality even 40 years from diagnosis due to many of the leading causes of death in the U.S. population," the study authors concluded, while noting that modifiable lifestyle and cardiovascular risk factors associated with reduced risk for late mortality should be part of future interventions.

AUTHOR COMMENTARY: "The Childhood Cancer Survivor Study continues to provide important insights into the long-term outcomes of the growing number of children successfully treated for cancer," said co-author Leslie Robison, PhD, Emeritus at St. Jude Department of Epidemiology and Cancer Control Chair. "The findings from the current analysis further emphasize the need to expand our efforts to reduce acute, chronic, and late-onset toxicities of treatment, particularly those toxicities that can directly or indirectly result in premature mortality."

MELANOMA

Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment

A recent preclinical study suggests that diet and probiotics can boost melanoma immunotherapy response (Cell 2023; doi:10.1016/j.cell.2023.03.011). With an increasing number of cancer patients using probiotics, including those undergoing immune checkpoint inhibitor treatment, it is important to understand their potential impact.

The study demonstrated that Lactobacillus reuteri stimulates cancer-killing T cells by secreting a compound called indole-3-aldehyde (I3A). When mice with melanoma were given a diet rich in the amino acid tryptophan, which the bacteria convert to I3A, immunotherapy drugs had a stronger effect on restraining tumor size and prolonging survival, according to the study authors. The findings lay the foundation for additional clinical trials to evaluate whether I3A treatments or combining probiotics and diet could help improve outcomes among melanoma patients who are undergoing immunotherapy.

AUTHOR COMMENTARY: "This paper shouldn't serve as a recommendation, but as an initiation. We hope it will spark other studies that investigate how diet affects immunity and cancer outcomes," said senior author Marlies Meisel, PhD, Assistant Professor in the Department of Immunology at University of Pittsburgh's School of Medicine and member of the Cancer Immunology and Immunotherapy Program at UPMC Hillman Cancer Center. "My lab is interested in understanding whether holistic approaches, such as diet or lifestyle changes, could enhance the efficacy of immunotherapy and other cancer treatments. I think it's empowering for patients that they could make these changes themselves-of course, after careful clinical consideration-and have some control over their treatment journey, rather than being entirely at the mercy of the health care system."