Decades of successful cancer research has led to the development of immunotherapies, such as monoclonal antibodies (mAb) and CAR-T cell therapies, often leading to dramatic improvements in patient outcomes, but oncologists still have a basic question. Which relapsing patients should get monoclonal antibody therapeutics and which will do better on chimeric antigen receptor T cell (CAR-T)-based therapies?

“Oncologists tend to be practical,” said Crystal L. Mackall, MD, Stanford University Medical School. “Given the ease of delivery for monoclonal antibodies versus CAR-T therapeutics, there is a tendency to use monoclonals first and reserve CAR-Ts for patients who progress. That may not be the best approach.”

Mackall offered that caution on sequential therapy while moderating the forum CAR-T Cell Therapy or T Cell Engager? on Sunday, April 11. Registrants can watch a replay of the session at their convenience through June 21, 2021.

The practical problem, Mackall said, is that resistance to both mAb and CAR-T therapeutics are associated with the emergence of antigen-negative and antigen-low variants. Starting with a less effective therapy, whether mAb or CAR-T, could diminish the potency of any subsequent therapy.

One approach, Mackall said, is to better define which patient populations with relapsed or refractory leukemia are better served by mAb therapies versus CAR-T based therapies. Clinical trial experience suggests that combination therapies could be even more effective.

Survival rates for acute lymphocytic leukemia (ALL) have doubled in recent decades, from roughly 30 percent in 1985 to 60 precent in 2020. Hagop M. Kantargian, MD, The University of Texas MD Anderson Cancer Center, credited a growing array of mAb and mAb combinations.

“Monoclonal antibodies come in many different flavors,” Kantargian said. “Unconjugated, conjugated with chemotoxins, conjugated with immunotoxins, bispecific T-cell engagers (BiTEs), and more.”

The growing universe of combination therapies has brought dramatic change. Five-year survival for Philadelphia chromosome-positive (Ph-positive) ALL at MD Anderson has gone from virtually zero in 1985 to 70 percent in 2020.

The survival increase has been driven by innovative treatment combinations such as Hyper-CVAD + ponatinib, blinatumomab + inotuzumab, dasatinib + blinatumomab, blinatumomab + ponatinib, and a growing focus on the treatment of minimal residual disease-positive cancers. Early-stage trials show up to 100 percent response rates.

Novel regimens such as hyper-CVAD + rituximab have boosted survival for Burkitt and Pre-B-ALL to nearly 80 percent, depending on the center. A shortened mini-HCVD + inotuzumab + blinatumomab regimen achieved complete response in 88 percent of older ALL patients, an objective response rate of 98 percent, and no deaths.

“Antibody therapy in ALL is here to stay and will continue to improve outcomes in these patients,” Kantargian said.

The same could be said for CAR-T and other engineered T cell therapies.

“We are in the era of immunotherapy for cancer, starting with interferon and IL-2 in the 1980s and now CAR-T and other synthetic biology products,” said Carl H. June, MD, PhD, FAACR, Perelman School of Medicine at the University of Pennsylvania.

The strength and timing of anti-cancer immune responses is a complex interplay of tumor, host, and environmental factors, he said. Synthetic biology and different methods of manipulating T cells using gene transfer and genome editing can create in vivo immune response to cancer that is far superior to recombinant proteins.

Synthetic biology is creating synthetic immunity, essentially putting the immune system on steroids, June said. Appropriately engineered CAR-T cells can redirect and restart immune recognition of tumors, increase resistance to tumor microenvironment factors that favor tumor growth, and even turn anti-cancer activity on and off as needed.

A recent proof-of-concept trial demonstrated the safety and feasibility of engineering the individual human genome to introduce multiple targeted genome edits at scale using CRISPR/Cas9 techniques. A single infusion of CRISPR/Cas9 triple-edited T cells in three patients with refractory cancer resulted in stable disease with no cytokine release syndrome (CRS) or severe adverse events. Edited T cells persisted at least six months and there was no evidence of autoimmunity.

CAR-T and T cell engager (TCE) therapies are associated with similar adverse events, CRS and neurotoxicity. Proponents of CAR-T and TCE approaches  claim superior clinical effect. There is no clear winner at this point, June said, while a combined CAR-T + TCE approach has already shown clinical benefit over either approach individually.

“We will see many combinations of cell-based therapies that are synthetically engineered, including recombinant proteins, checkpoint inhibitors, TCEs, oncolytic viruses, stem-cell transplants, vaccines, cytokines, and targeted small molecules,” June predicted.

“The cancer paradigm is changed from “cut it out-burn it out-poison it” to multimodal immunotherapy that reeducates the immune response to treat tumors as non-self and unleash the immune system brakes with greater specificity, memory, durability, and infectious anti-tumor activity. This is a very exciting time for the field.”