Learning from history – Umoja’s approach to overcoming CAR T therapy treatment challenges and limitations
Ten years ago, a little girl was in the battle of her life against a foe she couldn’t possibly comprehend. Two years previously, she was diagnosed with acute lymphoblastic leukemia at the age of 5. No parent wants to receive the news that their child has a potentially lethal disease, but for the majority of parents of children with leukemia, they are told that the chances of cure are quite high with a combination therapy approach that lasts several years. Unfortunately, Emily and her family were not so lucky, and her disease returned and was resistant to all subsequent available treatments.
Ultimately, Emily was the first child to receive a revolutionary new therapy called CAR T cells, which had been engineered from her own (autologous) white blood cells to recognize a protein on her cancer cells and, hopefully, clear her body of her leukemia. She received the CAR T cells in 2012 and had a very rocky clinical course. This included a potentially fatal side effect called cytokine release syndrome, or CRS. Further innovations in the care of patients receiving cellular therapies identified interleukin-6 (IL-6) as an important biologic mediator of this and other side effects. Importantly, scientists and researchers discovered that blockade of IL-6 from its receptor could help ameliorate the symptoms of CRS and potentially save lives. In the case of Emily, it did just that.
Now ten years later, Emily remains in remission from her leukemia, and the field of cellular therapy has made huge strides in treating patients, both children and adults, in the treatment of hematologic malignancies. There are now five products in the US approved for the treatment of such cancers, including some leukemias, lymphomas, and multiple myeloma. As these products have moved forward from clinical trial to commercialization, many roadblocks to patients receiving these therapies have arisen. These include the need for cell collection, a manufacturing time that can be anywhere from days to months, potentially requiring alternate therapies to keep their cancer “in check” while that uncertain manufacturing takes place, and the need for so-called “lymphodepleting” chemotherapy or conditioning to ensure the cells are accepted by the patient. Finally, the significant cost associated with this process and labor/resource-intensive manufacturing processes limit the number of patients who might benefit from these therapies in the long term. Still, to date, many people like Emily have benefited from the development of these groundbreaking treatments.
In terms of sheer numbers, solid tumors such as breast, lung, and others are much more common than blood cancers in the overall population. Unfortunately, getting these cellular therapies to solid tumor patients has faced many roadblocks, both biologic and logistic. As clinical trials have been initiated with so-called “ex vivo” autologous cell therapies, like the ones approved for blood cancers so far, researchers have discovered that solid tumors are much more complex in terms of the environment in which solid tumor cells “live”. This tumor environment makes them much more resistant to cell killing by CAR T cells, as they tend to suppress the activity of the immune system in general, which is how they take hold in the first place. This puts CAR T cells at a disadvantage in the treatment of these tumors. Many researchers and private companies are working very hard to unlock the key to this suppressive tumor environment to make CAR T cells more effective in solid tumors.
Unfortunately, even if the biologic hurdles are overcome for these cancers, the burden of manufacturing and administering autologous cell therapies along with preparative lymphodepleting chemotherapy must be addressed. At Umoja, we are taking a unique approach to conquer these challenges and are carefully designing a platform to address each of these issues. Our VivoVec™ technology is designed to be off-the-shelf, ready when a patient needs it. It should allow patients’ own bodies to make CAR T cells, without the need for ex vivo manufacturing. Next, the rapamycin-activated cytokine receptor (RACR™) system, delivered to the patient’s immune cells by VivoVec™, works in concert with rapamycin, an FDA-approved medication, to provide both a proliferative signal to transduced T cells as well as allowing for suppression of a potential immune response to the patient’s new CAR T cells. This should remove the need for lymphodepleting chemotherapy associated with most cellular therapies. Finally, a portfolio of bispecific engagers, or TumorTags™, are being developed to allow the CAR T cells to attack multiple targets simultaneously on both tumor cells as well as the tumor environment to give CAR T cells an advantage biologically to overcome CAR T cell suppression and, ultimately, lead to better efficacy while maintaining patient safety.
We and others around the world are working very hard to combat cancer in a way that is safe, effective, and equitable for all members of society. We stand on the shoulders of patients and scientists who have contributed to the body of knowledge that guide our efforts, and we are committed to transforming the treatment of blood cancers and solid tumors.