Immunotherapy has become a standard of care in treating high-risk, early-stage breast cancers, yet it has had limited success in shrinking tumors. New biomarkers that can improve outcomes for patients are urgently needed.

Now, a study led by researchers at the Vanderbilt-Ingram Cancer Center has found that repeated blood sampling — essentially, a liquid biopsy — can assess and predict the evolving antitumor immune response to therapy.

This minimally invasive and cost-effective alternative to tissue biopsy offers “an accessible tool for tailoring treatment strategies in breast cancer,” they reported April 22 in the journal Science Translational Medicine.

The researchers performed RNA sequencing on 546 peripheral blood samples from 160 patients with high-risk, stages 2 or 3 breast cancers negative for human epidermal growth factor receptor 2 (HER2) during treatment with either chemotherapy alone or in combination with immunotherapy.

Justin Balko, PhD, PharmD, professor of Medicine and Pathology, Microbiology and Immunology at Vanderbilt Health and the paper’s corresponding author, acknowledged several co-authors — investigators from the nationwide I-SPY2 clinical trial — who, among other contributions to the study, provided the blood samples.

Molecular profiles of tissue plus circulating tumor DNA can better guide cancer care

Co-author Laura Esserman, MD, MBA, director of the Breast Care Center at the University of California, San Francisco, is principal investigator of the I-SPY2 trial, which is assessing novel treatment strategies for subsets of breast cancer based on their molecular characteristics (biomarker signatures). Vanderbilt Health is among 42 trial locations.

Cell-free DNA testing, another form of liquid biopsy, is routinely used clinically for detection, diagnosis and therapeutic monitoring of a variety of malignancies.

Balko and his colleagues sampled the transcriptome, the transcription of genes involved in the clonal expansion and activation of antitumor immune cells called T cells. They found it predicted response to the immunotherapy drug pembrolizumab.

While validation is needed, this new liquid biopsy has the potential to “guide immunotherapy decision-making, tailor treatment regimens, and advance precision oncology, not only in (breast cancer) but potentially in other solid tumors as well,” the researchers concluded.

The paper’s first author, Xiaopeng Sun, PhD, is now at Merck. Co-authors at Vanderbilt Health are Andres Ocampo, Jacey Marshall and Julia Steele, graduate students in the Vanderbilt Program in Cancer Biology, and Susan Opalenik, PhD, senior research supervisor in the Balko lab.

The study was supported in part by National Institutes of Health grants P50CA098131, PO1CA210961, R01CA255442, U54CA274502, P30CA082103, P30CA068485 and NIH/NCI Imaging grant 28XS197 P-0518835), a Department of Defense Era of Hope Award, the Breast Cancer Research Foundation, Breast Cancer Research — Atwater Trust, Stand Up To Cancer, the California Breast Cancer Research Program and Give Breast Cancer the Boot.

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Hematologists with Vanderbilt-Ingram Cancer Center have published strategies for implementing outpatient treatment programs for bispecific antibodies, an immunotherapy that can cause adverse reactions.

The recommendations, published recently in JCO Oncology Practice, detail a comprehensive overview of the potential risks, treatment options for dealing with reactions, prophylactic protocols to prevent them from occurring, and the roles of an interdisciplinary care team within an outpatient program. The team at Vanderbilt-Ingram has expertise in outpatient care models for immunotherapy treatment because Vanderbilt-Ingram was among the first in the nation to establish outpatient protocols for another personalized immunotherapy, CAR-T.

Bispecific antibodies (BsAb) utilize engineered antibodies, molecular spikes, which bind to both cancer cells and immune cells, activating a patient’s T cells to attack hematologic malignancies. With CAR-T (chimeric antigen receptor T-cell therapy), T cells are harvested from a patient, then reengineered to recognize and destroy cancer cells before being infused back into the patient’s body. Both therapies can elicit strong immune responses with complications that pose risks, including cytokine release syndrome, a potentially life-threatening reaction that can damage healthy tissues and organs.

For this reason, the BsAb and CAR-T therapies typically require inpatient monitoring, which can be an economic and logistical burden for both patients and hospitals.

“Bispecific antibodies are a major advance in the field of cancer immunotherapy,” said the article’s corresponding author, Bhagirathbhai Dholaria, MBBS, associate professor of Medicine. “This class of drugs is available off the shelf, which makes them ideal for utilization in the community settings. In this article, we have provided a comprehensive framework to establish an outpatient bispecific antibodies program, especially for community practices, which do not have an already established CAR-T program. Our strategy has the potential to greatly reduce the logistical and financial burden during step-up dosing of bispecific antibodies while maintaining safety of the patients.”

The protocols suggested are for seven BsAb therapies that have been approved by the Food and Drug Administration for non-Hodgkin lymphoma and multiple myeloma. They address potential complications, including cytokine release syndrome, infections, cytopenia, tumor flare reactions, and immune effector cell-mediated neurotoxicity syndrome.

The authors noted that while outpatient programs for CAR-T were established before bispecific antibodies, CAR-T poses higher risks for adverse reactions. Their recommendations prioritize early recognition and intervention for these complications, particularly in the first cycle of treatment with BsAb when most cytokine release syndrome events are likely to occur.

The paper provides an infrastructure and workflow guide for how clinicians can work with patients to implement monitoring and address care needs. They also stress the importance of educating both patients and family/friend caregivers about proper protocols for remote monitoring.

The article’s additional authors are Kian Rahbari, MD, and Raul del Toro Mijares, MD, Kathryn Kennedy, RN, Leslie Mader, RN, Salyka Sengsayadeth, MD, Reena Jayani-Kosarzycki, MD, James Jerkins, MD, Andrew Jallouk, MD, Tae Kon Kim, MD, Shakthi Bhaskar, MD, Vivek Patel, MD, Brittney Baer, RN, Sarah Moseley, RN, David Morgan, MD, Bipin Savani, MD, Adetola Kassim, MD, Muhamed Baljevic, MD, and Olalekan Oluwole, MD.

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Some cancer patients experience durable remissions from immune checkpoint inhibitors that spur their T cells to attack cancer cells, but these immunotherapies can also cause reactions.

One of the adverse effects of these treatments is skin reactions known as cutaneous immune-related adverse events (cirAEs), although it is not known how often they morph into a chronic condition. Research led by investigators at Vanderbilt University Medical Center published in JAMA Dermatology provides insight into chronic cirAEs. They recommended long-term follow-up for patients by dermatologists familiar with cirAEs and consideration of corticosteroid-sparing treatment options.

“Understanding the potential for side effects to become long-lasting has been an important advance recently, and managing them more effectively is a key unmet need,” said the study’s corresponding author, Douglas Johnson, MD, MSCI, professor of Medicine, holder of the Susan and Luke Simons Directorship, and co-leader of the Translational Research and Interventional Oncology Research Program at Vanderbilt-Ingram Cancer Center.

The investigators reviewed the records of 318 patients from a previous study who had been treated with immune checkpoint inhibitors. Of that number, 100 or 31% developed cirAEs with the skin conditions becoming chronic for 24 of the patients — nearly 8% of the full cohort. The study looked at 21 of those patients who underwent detailed follow-up. Another 31 patients were added from Vanderbilt clinics who were treated for cirAEs.

The 52 patients had received either pembrolizumab, nivolumab, ipilimumab or anti-PD1 and CTLA4 combination therapy.

The types of skin reactions varied, with 15 experiencing pruritus or itchy skin, 12 experienced morbilliform eruptions or drug-induced skin rashes, 12 experienced dermatitis or inflamed and scaly rashes, eight experienced bullous pemphigoid-like eruptions (fluid-filled blisters that resemble a rare autoimmune skin disease), five experienced eczema, four experienced lichenoid (flat-topped, scaly lesions), two experienced psoriasiform (breakouts that resemble psoriasis), and one experienced acneiform or acne-like eruptions.

The median duration of cirAE from treatment cessation was 446 days. Rare cases lasted more than five years.

Other Vanderbilt authors on the study included the study’s lead author, Kylie Fletcher, BS, Rachel Goodman, MD, MBA, J. Randall Patrinely, MD, MBA, and Anna Dewan, MD, MHS.

The research received support from Medical Scholars at Vanderbilt University School of Medicine, the Susan and Luke Simons Directorship, the James C. Bradford Jr. Fund in Melanoma Cancer Research and the Van Stephenson Memorial Cancer Research Fund.

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The study reported in the journal Nature provides a mechanistic explanation for the obesity paradox that obesity can contribute to cancer progression but also improve response to immunotherapy.

Vanderbilt researchers are working to better design immune therapies that attack tumors without also attacking healthy normal tissue in patients.

GE Healthcare has awarded researchers $2.5 million in funding to develop PET tracer that will determine the effectiveness of immunotherapy in patients early in their treatment course.

Combining immunotherapy and radiation therapy may be a powerful treatment approach for castration-resistant prostate cancer.

Researchers are chronicling rare but serious toxicities that may occur with immune checkpoint inhibitors, the most widely prescribed class of immunotherapies.

A recent study in the journal Cancer Research demonstrates that a RIG-I agonist has potent immunogenic and therapeutic effects in breast cancer.

Patients who received atezolizumab in addition to standard chemotherapy lived two months longer than those treated with chemotherapy alone, according to a recent study published in the New England Journal of Medicine.