Krystle Karoscik

Immunotherapy has revolutionized cancer treatment strategies for a variety of hematological and solid tumor malignancies. Two main therapeutic approaches, chimeric antigen receptor T-cell therapies (CAR-T) and checkpoint inhibitors (CPI), have emerged as promising immunotherapies and have been successful at improving patient prognosis. While the development of next-generation CAR-T and CPI strategies continues to expand upon an already diverse immunotherapy landscape, there are significant differences that can influence the conduct of early-stage clinical trials using these approaches.

CAR-T therapy is a type of immunotherapy that genetically modifies a patient’s own T-cells to recognize and destroy cancer cells. While there are many clinical trials underway for a variety of tumor types, CAR-T therapy has emerged as a promising strategy for the treatment of blood cancers. In comparison, CPI therapeutics work by blocking checkpoint proteins on T-cells or tumor cells from binding with partner proteins, that enhances T-cell killing of cancer cells. CPI drugs have been approved in a variety of cancer types.

Both immunotherapies are currently being used in early-stage clinical trials for cancer research. However, a simple way to describe the comparison between CAR-T and CPI is “process versus product.” The investigational drug in a CAR-T trial is the end product from a manufacturing process in which T-cells are collected from patients via apheresis, then genetically engineered to express chimeric antigen receptors on their surface. The modified T-cells are expanded to significant quantities, frozen, then infused back into the patient; this process is similar to a blood transfusion. Patients need to be hospitalized for the infusion and will remain hospitalized for a few days or weeks dependent on their condition as well as the risk of side effects. In comparison, CPI drugs are most commonly a monoclonal antibody product that is typically administered by an IV infusion over several hours to patients in the outpatient setting. While both immunotherapeutic approaches have yielded successful results for patients, there are risks and challenges of each that should be considered.

CAR-T has shown tremendous success in adult and pediatric patients. Novartis made headline news with the launch of Kymriah in 2017 as a one-time treatment for B-cell acute lymphoblastic leukemia (ALL), showing a remission rate of greater than 80% after three months in patients who do not respond to standard of care treatments. A second CAR-T cell therapy, Yescarta, was approved for patients with large-B-cell lymphomas whose cancer has progressed after receiving at least two prior treatment regimens.

More recently, in late July, CAR-T drug Tecartus was approved by FDA for the treatment of mantle cell lymphoma in patients who have not responded to other treatment types or relapsed following treatment.

The CAR-T therapy landscape has been most effective on blood cancers, but what progress has been made on solid tumors?

Many strategies have emerged to improve the efficacy of CAR-T therapies for solid tumors, however, several challenges have been identified in recent years. These include intricacies of solid tumors and their locations in the body, hostile tumor microenvironments, toxicities, and undesired antigen specificity. Alternative next-generation approaches for the treatment of solid tumors are currently in development.

One of the major challenges for use in CAR-T therapy is the inappropriate targeting of CARs that cause adverse events, including cytokine release syndrome and the increased incidence of neurologic events. Most of the CAR-T cell target antigens seem not to be tumor-specific and shared by normal cells. Therefore, antigen specificity becomes a crucial factor for CAR-T therapy.

As with CAR-T therapies, CPIs have also proven efficacious, while also bearing risks. There are a number of CPI drugs on the market that have shown anticancer activity against a variety of cancer types. Evidence of benefit has been reported when CPIs are combined with certain chemotherapies and radiation treatments, as well as other immunomodulatory drugs. CPIs have also shown to be effective in the adjuvant setting for some cancers. Major risks associated with CPI include a variety of immune-related adverse events, including graft-versus-host disease (GVHD) and widespread inflammation.

What does the immunomodulatory therapy pharma landscape look like?

Organizations working on immunomodulatory therapies include large pharmaceutical companies as well as emerging biotechnology companies with exciting new approaches for patients. There are also many startups and university spinouts focused on novel approaches to immunomodulation to treat cancer patients.

Highly innovative universities and research centers, such as the University of Pennsylvania and the City of Hope National Medical Center, not only provide new technologies for evaluation, but they also provide the infrastructure for the manufacture and testing of new immunotherapies for future commercial development.

What else should be considered when it comes to these clinical trials?

Consider using an oncology-focused CRO to support the improved and accelerated development of novel immunotherapies. It is critical that the CRO be familiar with the logistics for CAR-T and CPI trials that can vary by therapeutic type, patient population, and indication. Also, it is imperative that the medical monitors and the clinical team need to be familiar with the type of trial, indications, patient profiles, safety concerns, and operational logistics. For example, patients may experience unanticipated adverse events with each immunotherapy, meaning that it is critical that the clinical team be experienced and fully prepared throughout the study. Since having extensive management experience for complex clinical trials is key, a CRO’s strategic expertise can help keep clinical trials operational, while providing optimal patient safety and efficacy.

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Distinguishing CAR-T and CPI approaches and the clinical trial challenges and complexities associated with each.

Krystle Karoscik

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Immunomodulators and Cancer Research