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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Interim results from an ongoin​​g Phase 1 clinical trial for an off-the-shelf CAR-T therapy indicate that no dose-limiting toxicities or severe cytokine release syndrome instances occurred in an early and limited cohort of patients. 

The results were reported in Nature Communications on Nov. 24. Vanderbilt-Ingram Cancer Center accrued the most patients nationwide for the clinical trial for P-BCMA-ALLO1 – a chimeric antigen receptor T cell therapy (CAR-T) derived from healthy donors’ white blood cells. Currently, all CAR-T therapies approved by the U.S. Food and Drug Administration are autologous or made individually from each patient’s own reengineered T cells. An off-the-shelf or allogenic therapy derived from healthy donors would expedite the manufacture of this immunotherapy and make it readily available to patients, allowing them to start treatment sooner and expanding access to those patients not healthy enough for their own T cells to be reengineered. 

T​​he results reported in the Nature Communications study include​ data​ from 11 patients who received enhanced lymphodepletion, which is short-course chemotherapy to reduce the number of lymphocytes and create a favorable environment for the CAR-T therapy. Clinical analyses of patient responses and additional enrollment continue in the ongoing phase 1 trial. 

“P-BCM-ALLO1 differs from other CAR T-cell products due to the non-viral vector gene editing technology used during manufacturing. This approach allows P-BCMA-ALLO1 to retain T-cell memory phenotype compared with an activated T-cell phenotype common with CAR-T products using a viral-vector,” said Bhagirathbhai Dholaria, MBBS, associate professor of Medicine at Vanderbilt University Medical Center, who is leading the clinical trial at VUMC and is one of the study’s lead authors. 

P-BCMA-ALLO1 has exhibited characteristics that are crucial for CAR-T therapy because it is typically a one-and-done treatment. The study’s authors noted that the therapy had an optimal potency profile characterized by a strong memory phenotype and significant proliferative capacity. They stated that it “functions as a prodrug, conferring multipotency to rapid expansion and control of the tumor.” 

The interim results do not include enough data to make determinations about clinical efficacy of P-BCMA-ALLO1 because of the limited number of participant responses analyzed at this point, but Dholaria has observed positive results in individual patients. 

​​​​​“I have observed remarkable response rates in heavily pre-treated multiple myeloma with minimal cytokine release syndrome or neurological side effects,” he said. “In this study, I have also treated patients who have previously failed autologous CAR-T therapies or bi-specific antibodies. The ongoing study will help determine optimal cell dose and conditioning regimen for P-BCMA ALLO1.” 

The clinical trial for P-BCMA-ALLO1 is continuing to recruit participants. For more information about the clinical trial at Vanderbilt-Ingram Cancer Center, call 800-811-8480 or 615-936-5847 or email cip@vumc.org. 

“These are exciting times for our patients,” said Olalekan Oluwole, MBBS, MPH, associate professor of Medicine, who leads the cellular therapy research program at Vanderbilt-Ingram. “P-BCMA-ALLO1 CAR-T was engineered for the safety of patients. Furthermore, being an off-the-shelf CAR-T product meant we could get it to our patients almost immediately.” 

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