Engineered T cells provide more opportunities for cancer therapy

Immunotherapy is “a revolution in cancer therapy,” according to Crystal L. Mackall, MD, director of the Stanford Center for Cancer Cell Therapy and the Parker Institute for Cancer Immunotherapy at Stanford, associate director of the Stanford Cancer Institute, and a professor at Stanford University. Dr. Mackall delivered the Lila and Murray Gruber Memorial Cancer Research Award and Lectureship during Sunday’s plenary. During her session, “Engineering T Cells for Cancer Therapy,” Dr. Mackall said she believed CD19-CAR therapy was a “watershed” event in cancer treatment. It marked a turning point.

Crystal L. Mackall, MD

Paradigm shift in therapy

“Using the immune system to treat cancer is creating a paradigm shift in cancer therapy. This is largely driven by the activity of checkpoint blockade now observed across an increasing array of cancer types,” she said. “But despite these successes, responsiveness to checkpoint blockade varies widely, and while the numerous factors that impact responsiveness to checkpoint blockade continue to be elucidated, one major factor is the level of mutational load within the tumor itself. Tumors with higher mutational loads tend to be ‘checkpoint responsive,’ while those with lower burdens are not.”

Checkpoint blockade is only one of a number of therapeutics that amplify immune responses and Dr. Mackall anticipates the combinations of such immune response amplified in the coming years will increase the efficacy of this approach.

“Alternatively, we now have available, through the use of synthetic biology, an increasing array of immunotherapies that do not rely on inherent immunogenicity and can be described as immune response initiators,” she said. “Monoclonal antibodies were the first of this class to definitely demonstrate activity in cancer and recently there have been increasing efforts toward the use of engineered T cells, for which CAR T cells are a prototype.”

In 2010, CD19-CAR therapy was shown to have induced complete regression of lymphoma for the first time. In 2011, a complete regression in leukemia followed.

Advancements in CD19-CAR therapy

Dr. Mackall highlighted several groundbreaking facts about CD19-CAR therapy in her plenary:

  • It was the first FDA-approved cell therapy for the treatment of cancer.
  • It was the first gene therapy approved in the U.S.
  • It has an unusual developmental path in that it was approved in children prior to adults.
  • It was the first therapy with an outcome-based payment model, but it also has the most expensive sticker price per dose of all cancer therapeutics.
  • It eradicates high burdens of chemo-resistant cancer.
  • Approximately 50% of responding patients relapse within about one year, most with CD19 negative leukemia.
  • CD19neg relapse also occurs following CD19-CAR for lymphoma.

Since it was developed, therapies based on the original CD19-CAR therapy have continued to evolve. CD19-based CARs are now FDA- and European Medicines Agency (EMA)-approved for patients up to the age of 26 with relapsed/refractory B-ALL. It’s also FDA- and EMA-approved for adults with relapsed/refractory large B cell lymphomas. Trials are currently underway to test earlier stage treatment in B-ALL and lymphoma.

CD19-CAR therapy comes hand-in-hand with two major toxicities: Cytokine release syndrome and neurotoxicity. Improved supportive care and more clarity on appropriate dose have lowered the morbidity and mortality associated with the therapy. In registration trials, treatment-related mortality ranged between 1 and 3%.

New on the scene, said Dr. Mackall, is CD22, which she has been working to implement.

“CD22 is a new, potent CAR for B-ALL and is likely to serve an increasingly important role as the incidence of CD19 B cell malignancies is increasing by the advent of CD19-directed therapies.”

As the high response rates with CD22-CAR indicate, shesaid “CD19-CARs are not a ‘one trick pony.’” Researchers are currently working on being able to combine CARs, which would allow CD19 and CD22 therapies — or others — to work in combination to target mutations.

What’s ahead?

In the next five years, said Dr. Mackall, we can expect clinical testing of more complex and sophisticated CARs. These include bispecific CARs, tri-specific CARs, quad-specific CARs, regulatable CARs, universal CARs, gate CARs, switch receptor CARs, exhaustion-resistant CARs, and more.

Dr. Mackall said the challenges facing CAR-T cell therapy for solid tumors are low/heterogeneous antigen expression, T cell exhaustion, a suppressive microenvironment, and insufficient tumor trafficking. There are challenges on the manufacturing side of the equation as well. Its high cost, limited availability, and manufacturing time delays are all obstacles. Overall, though, she said to expect the field to grow dramatically in the next five to 10 years.

“Continued positive clinical results will continue to drive technological advances and decreased cost of goods,” said Dr. Mackall, “which will, in turn, drive costs down and increase accessibility in coming years.”

 

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