While immunotherapy has been successful for a number of aggressive cancers, acute myeloid leukemia (AML), a hematologic malignancy with dismal outcomes, has no currently known immunotherapy targets. In a recently published study in Nature Cancer, Arun Wiita, MD, PhD reports the hurdles and successes in developing a novel target using CAR-T cells developed specifically for AML.
Describe the work and explain how will this help patients or providers in the field
In this work we describe what we believe are two important advances that will benefit patients. First, we showcase a totally new technology to profile the 3-D shapes, or "conformations", of protein molecules on the surface of cancer cells. This technology is important because the most exciting new therapies in cancer engage the immune system to attack cancer cells based on these surface protein targets.
Numerous circulating blasts with monoblastic cytomorphology and gently folded nuclei. Image courtesy the American Society of Hematology.
Therefore, our technology ideally unlocks an entirely new class of immunotherapy targets based on protein shape. Second, we specifically develop a therapy targeting one of these protein shapes that is only present on tumor cells and not on normal cells. Our new therapy is designed to treat the deadly cancer acute myeloid leukemia, a disease that desperately needs new treatments. While much work remains to be done, the approach we describe has the potential to be turned into a real therapy to benefit patients.
“This new level of identifying and discriminating targets is an exciting advance not only for blood cancer but potentially any cancer, with the hope of developing safer, more effective therapies for patients.”
What excites you about this discovery?
We take advantage of an emerging technology called "CAR-T cells", where a patient's own immune cells are engineered to recognize and fight cancer. CAR-T cells have been very effective in some types of blood cancer, but for acute myeloid leukemia one of the major challenges has been the lack of surface protein targets on tumor cells that can allow for elimination of tumor cells while also sparing critical, normal blood cells.
We believe that the target we discovered here, called the active conformation of integrin beta-2, has the potential to overcome these prior hurdles and make a best-in-class safe and effective therapy. UCSF is one of the world's leaders in the development of T-cell engineering technologies. We thus have the knowledge, environment, and infrastructure at our institution to potentially turn this discovery into a true therapy that benefits patients.
How does this work capitalize on previous work either you have done personally, or has been done by UCSF colleagues?
In our lab we had previously profiled the cell surface of other types of blood cancer to find new therapeutic targets. Indeed, we have made a CAR-T cell against one of these new targets we discovered, specific for a childhood blood cancer, that we will soon bring to a clinical trial at UCSF. This previous work has been supported by the UCSF Living Therapeutics Initiative and several other funding sources. The new work we publish now greatly extends these prior target discovery approaches.
Previously, we could only identify promising targets based on the relative increase of the protein on the surface of cancer cells vs. normal cells. Now, we can find new targets based on the shape of the surface protein that is specific for tumors, even if the protein is present in a different shape is present on normal cells. This new level of identifying and discriminating targets is an exciting advance not only for blood cancer but potentially any cancer, with the hope of developing safer, more effective therapies for patients.
How can this work be expedited with increased funding or collaborations?
Turning our proof-of-principle CAR-T cell into a true therapeutic is a major undertaking. Going from our current stage in the laboratory to the starting phases of a clinical trial requires in the range of $5-7 million in resources. We are currently actively seeking further financial support to bring this exciting new therapy to acute myeloid leukemia patients at UCSF who have very high unmet need for new therapies. If successful, our goal will be to partner with others to expand this therapy to AML patients across the country and around the world.