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Advances in Cellular Therapies for Hematologic Malignancies Highlighted at ASH 2019

February 2020 Vol 13, Special Issue - Conference Highlights ASH
Wayne Kuznar

Orlando, FL—The emergence of cellular immunotherapy for a broad array of hematologic malignancies was featured prominently at ASH 2019. The development of adoptive therapy with T-cells that target oncologic malignancies was the subject of the E. Donnall Thomas Lecture “The Long Road to Develop Adoptive Therapy with T Cells That Can Effectively Target Acute Myeloid Leukemia (AML) and Other Malignancies,” delivered by Philip Greenberg, MD, Head, Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA.

Dr Greenberg highlighted the history of how T-cells have been engineered to fight AML and harness immunotherapy to eradicate cancer cells. He discussed the advances in engineering T-cells to acquire specificity and enhanced function to make T-cell therapy a valuable component of the treatment armamentarium.

Dr Greenberg’s work began in animal models and has progressed to using adoptive T-cells to target AML and solid tumors in clinical trials in humans. He told of his early work in treating patients at high risk for relapse after bone marrow transplant, in whom infusing T-cells prevented 12 patients from having a relapse even 5 years later versus those in the control groups.

This is reflected in the progress made between his early comment upon joining Fred Hutchinson Cancer Research Center many years ago and the reality today. In those early days, Dr Greenberg thought, “We would eventually be able to do away with bone marrow transplantation and replace it with T-cells that specifically target cancer. Now, we are getting increasingly close to making that rather brash statement a reality,” he said.

Dr Greenberg noted the importance of maintaining T-cell persistence in preventing relapse. One day, he said, T-cell survival may be enhanced by recruiting helper T-cells that could be engineered to recognize the same target, replacing mechanisms that promote T-cell death with robust co-stimulatory signals.

Several studies presented at the meeting featured in this issue highlighted the rapid advances being made to enhance chimeric antigen receptor (CAR) T-cell therapies.

First-generation CAR T-cell therapies primarily target CD-19 and induce long-term remission in approximately 33% of patients with B-cell lymphomas who have not responded to previous therapies. “We are now seeing efforts to enhance the effectiveness of CAR T-cell therapy by designing products capable of attacking multiple targets; expand the availability of cellular immunotherapy to other blood cancers such as multiple myeloma; and replace the complex manufacturing process required for CAR T-cell therapy with a uniform off-the-shelf product,” said Gary J. Schiller, MD, Director, Bone Marrow/Stem Cell Transplant Program, UCLA Health, Los Angeles, CA, who moderated a press briefing on CAR T-cell therapy.

An off-the-shelf dual-targeted antibody (mosunetuzumab) elicited durable responses in poor-prognosis non-Hodgkin lymphoma. Data from 270 patients with B-cell lymphomas that had recurred or not responded to a median of 3 previous therapies indicated that among patients with slow-growing lymphomas, 63% had objective ­responses and 43% had a complete response. The complete responses were long-lasting. With a median follow-up of 6 months since the first complete response, 83% of patients who achieved complete responses of their slow-growing lymphomas and 71% who achieved complete responses of their fast-growing lymphomas remain free of disease (see Mosunetuzumab, a Dual-Targeted Antibody, Shows Complete Remissions in Relapsed/Refractory NHL After CAR T-Cell Therapy).

Another off-the-shelf drug, based on natural killer cells, demonstrated comparable ability to kill cancerous white blood cells as standard CAR T-cells. When combined with rituximab, the natural killer cells eradicated cancerous white blood cells that were no longer responding to standard CAR T-cell therapy as a result of the loss of the CD19 antigen target.

In another study of CAR T-cell therapy, patients with multiple myeloma who had received a median of 5 previous therapies, and for whom standard-of-care treatments were no longer effective, had a clinical response rate of 100% and a stringent complete response rate of 66% when they received treatment with the investigational CAR T-cell therapy JNJ-4528, which targets BCMA, a protein that is frequently found on the surface of multiple myeloma cells (see Novel BCMA-Directed CAR T-Cell Therapy Had Excellent Responses in Heavily Pretreated Patients with Multiple Myeloma).

Dual-targeted T-cell therapy in hard-to-treat multiple myeloma induced remissions that lasted at least 7 months after the start of treatment in more than 3 of 4 patients with relapsed or refractory multiple myeloma. This treatment is the first CAR T-cell therapy to be genetically engineered to target BCMA and CD38, 2 proteins that are found on the surface of plasma cells (see Dual-Targeted CAR T-Cell Therapy Leads to Very High Response Rates in Relapsed or Refractory Multiple Myeloma).

Other featured studies offered insights into the impact of clinical trial inclusion criteria, calling into question criteria that may systematically exclude minorities and older individuals.

“Our ability to achieve tailored treatments and prevention relies on including a wide and heterogenous spectrum of individuals in clinical trials,” said Laura Michaelis, MD, Associate Professor, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, who commented on the first national study on this topic.

“We have an obligation to recruit people who are traditionally absent from trials, including groups such as women, older people, minorities, people living in poverty, and people who are chronically ill or who have comorbidities,” she said (see First National Study: Geographic Socioeconomic Disparities Mirror Substantial Gaps in Survival in Children with AML).

In another study, researchers showed that certain comorbidities in patients with AML do not affect treatment response or survival, even though these comorbidities are often used to exclude participants from clinical trials of AML treatments. The researchers examined records from 1040 patients with AML who received care at Cleveland Clinic from 2003 to 2019. They found no significant differences between African-American and white patients in treatment approaches, rates of response to treatment, or overall survival.

African Americans, however, were significantly more likely to have abnormal creatinine and creatinine clearance. Previous studies suggest that African Americans have higher creatinine levels than whites; thus, this laboratory value may falsely underestimate this subpopulation’s kidney function, potentially excluding them from studies that require normal creatinine or creatinine clearance values.

“These results suggest future AML trials may liberalize comorbidity and organ function eligibility criteria, which will likely improve recruitment rates and provide equitable access to investigational products,” said lead investigator Abby Statler, PhD, MPH, MA, Cancer Biostatistics, Cleveland Clinic, Shaker Heights, OH (see First National Study: Geographic Socioeconomic Disparities Mirror Substantial Gaps in Survival in Children with AML).

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Last modified: March 5, 2020
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