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September 21, 2017

Why CAR-T Therapies Don’t Work for Everyone Yet

Selecting the Best Type of T Cells for CAR-T May be Key to the Overall Efficacy of the Therapies

Why CAR-T Therapies Don’t Work for Everyone Yet

Colorized scanning electron micrograph of a T lymphocyte. T lymphocytes are extracted from a patient's blood at the beginning of a CAR-T manufacturing process [NIAID].

  • A patient’s own cells can be engineered to combat cancer. Called a “living drug”, the cells hunt and destroy cancer cells, sometimes adding years to the lives of individuals who previously had little hope.

    The newest treatment categorized as a living drug is called Kymriah (tisagenlecleucel). Developed by Novartis, it is the first FDA-approved chimeric antigen receptor T-cell (CAR-T) therapy, which has helped patients battle against a blood cancer called acute lymphoblastic leukemia (ALL). Kymriah is approved to help combat this cancer in children and young adults up to age 25 who have not responded to standard treatment or have suffered relapses.

    The drug is personalized, and is made from T cells taken from patients. The T cells are genetically engineered to express a receptor that is designed to target the protein CD19. This protein is found on B cells, and is found in abundance in patients with ALL and other types of leukemia and lymphoma. A patient’s engineered T cells target the protein, bind to them, and then destroy B cells—both those that are cancerous, as well as those that are healthy (all B cells have the CD19 surface protein). A single infusion of the drug costs $475,000.

    While CAR-T appears to be quite revolutionary, it doesn’t work for everyone. In fact, some of the patients in CAR-T investigational trials relapsed after treatment and eventually died.

    Approval of Kymriah was based on a clinical trial of the treatment in 63 children and young adults who had relapsed after or were resistant to previous treatments. Eighty-three percent of the patients went into remission; that means roughly 10 children didn’t respond to the treatment. In another study of a CD19-targeted CAR-T, this one on adults with ALL, 20 patients responded to the CAR-T, while 31 did not.

    “Why certain patients respond while others don’t is not well understood,” says David Porter, M.D., who studies CAR-T and leukemia at the University of Pennsylvania and is a colleague of Carl June, M.D. “There are some known reasons and then there are some hypotheses.”

    One idea is that the health of the T cells matter. If the T cells that are taken from the patient are old or have been damaged, they might not work well even after they have been engineered to home in on and destroy B cells. Another idea is that not all patients’ B cells carry the specific CD19 surface protein that is targeted. Instead, some of the B cells may have CD19-negative proteins, rendering the T cells with CD19 receptors useless. And, Porter says, the tumor cells may also still have the ability to suppress T cells.

    Jae Park, M.D., who specializes in leukemia research and treatment at Memorial Sloan Kettering Cancer Center in New York, says that the microenvironment of the tumor cells can prevent the engineered T cells from attacking and killing the malignant cells.

    To overcome these challenges with the treatments, researchers are looking for other CAR-T targets. One alternative is CD22. Like CD19, CD22 is expressed on B cells, and early studies indicate some success in helping patients combat their cancer, even after relapsing following treatment with medications targeting CD19. In explaining the results in a 2016 paper, Penn researchers Marco Ruella, M.D. and Dr. June write that CD22 represents an “attractive target” for B-ALL and non-Hodgkin’s lymphoma (NHL), and also for potential double-targeting of CD19 and CD22, which could help to prevent cancer cells from evading detection and destruction. Other CAR-T targets being studied are CD20, the Kappa light chain, ROR-1, and CD30.

    “Identifying other targets is a busy area of research,” Dr. Porter adds.

  • Making CAR-T Better

    Younger, less differentiated T cells are also an area of focus. Engineering naïve, stem cell memory or central memory T cells as part of the treatment is correlated with better long-term antitumor response as compared with effector T cells, the authors note. In turn, teams of researchers have been working on using different cytokines during the production of the engineered T cells to boost central memory T cells in the final treatment product, which would then be infused into the patient. Another possibility, Park says, is to modify the T cells further to include molecules that will spur the release of cytokines that prevent the tumor cells’ suppression of the T cells and help them to work more effectively.

    Many different teams of researchers, in affiliation with biotech companies, are developing CAR-T treatments, raising the question of whether the different processes used to generate the engineered cells affect the effectiveness of the treatment. Dr. Ruella told GEN in an interview that no head-to-head comparisons of the success rates of different CD19 CAR-T therapies have been done. But, he says, looking at the results of the independent studies done so far, there doesn’t appear to be an “optimal” manufacturing process, or one that produces more efficient CAR-T therapies that better target cancer cells.

    Dr. Ruella does note that having more CAR-T–based treatments approved by the FDA will allow doctors to choose which one is best for each patient or determine if a combination of CAR T-cells is needed to combat a patient’s cancer.

    In addition, researchers are also working on a “universal” CAR-T, known as an allogeneic option. This would be a generic T cell-based therapy not engineered on a one-to-one basis, but one that would be prepared with the necessary receptors and frozen, making it ready ahead of time for potential use in a larger group of patients. Right now, engineering CAR-T takes approximately 22 days. But, Porter says, if scientists can overcome any rejection of universal engineered T cells from the body, including the engineered T cells attacking their host, patients could potentially get access more quickly and more affordably (barring any holdups from insurance companies in terms of reimbursement and provided there are no difficulties getting the medication from a specialty pharmacy, from where these universal treatments would likely be dispensed). Nonetheless, having CAR-T therapies more readily available is “an exciting possibility,” Dr. Porter notes.

    While the development of universal CAR-T therapies certainly is exciting, right now, patients’ and insurers’ immediate concern is the nearly half-a-million-dollar price tag for Kymriah. Novartis has said it plans to charge for the treatment only when the drug proves to be effective one month following infusion. Clinical trial data, however, show that patients can improve and then relapse after taking the drug, which has led to a call for a longer grace period—perhaps a year or even two of remission—before patients would be required to pay for treatment.

    In the meantime, the complicated manufacturing process for personalized CAR-T treatments is driving researchers to continue to develop even better, more targeted, CAR-T therapies.

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