An oncologist provides insight on his experience with using CAR-T therapy in the clinic and his prediction for the future of this revolutionary treatment.
Jae Park, MD, is a hematologist-oncologist, at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York, who is leading a clinical trial using chimeric antigen receptor (CAR)-T cells in the treatment of patients diagnosed with chronic lymphocytic leukemia (CLL). Park is also a part of trials investigating CAR T-cell treatment in patients with acute lymphoblastic leukemia (ALL).
In an interview with Evidence-Based Oncology™ (EBO™), Park described how the treatment manipulates the body’s immune system, reviewed some of the challenges that the field is currently faced with, and predicted what the future holds for CAR-T cells.
EBO™: Can you explain the leukapheresis process that is necessary for CAR T-cell treatment?
Park: CAR is an artificial T-cell receptor that is genetically engineered by combining a binding domain from a monoclonal antibody that is fused to a T-cell receptor. So the chimera binds like an antibody but acts like a T cell, and that’s where the name “chimeric antigen receptor” originates. It allows the T cell to recognize and bind a tumor, just like an antibody would. It then allows a universal applicability of this type of therapy; so once you create a CAR against a specific tumor antigen, you can modify the T cells—either the patient’s own T cells or donor T cells—to express the chimeric antigen receptor, which is now reeducated or reengineered to recognize a specific tumor antigen on a cancer cell better.
Once infused into the patient, these T cells traffick to the site of the tumor and they start eradicating the tumor cells. That’s the basic mechanism by which CAR-T cells function.
Leukapheresis, which is sometimes called apheresis, is the process of collecting white blood cells (WBCs). The process is very similar to that of platelet donation—the patient is hooked up to a machine with 2 catheters, 1 in each arm. The machine filters and collects only the WBCs while the rest of the blood components are returned to the other arm. The entire process can last between 2 and 4 hours, the rate-limiting steps being the rate of blood flow and the volume of blood that needs to be collected.
Autologous or patient-derived T cells are the most commonly used form of CAR-T cells, so the patients are the ones who undergo leukapheresis.
EBO™: Cytokine-release syndrome, a typical reaction to CAR T-cell treatment, can drain a patient—both physically and emotionally. Can you explain why the patient’s immune system generates this massive response? How is it typically managed?
Park: Cytokine-release syndrome, or CRS as it is commonly called, is the body’s response to the T cells attacking the tumor cells. As the T cells are getting stimulated, and expand upon recognition of cancer cells, they release inflammatory proteins called cytokines—this is our body’s typical immune response to fight off infection. Just as a viral or bacterial infection results in fever or issues with breathing or blood pressure, where the T cells release pro-inflammatory cytokines as a way to alert or recruit the body’s endogenous immune cells to fight the infection.
Similarly, in this case, as the T cells are infused and are trafficked to the site of the tumor, they recognize the cancer cells, are activated, and they release pro-inflammatory cytokines. The body’s reaction to this is the patient gets a high fever, and experiences low blood pressure or breathing difficulties. If the reaction is very severe, the patient may need to be managed in an intensive care unit.
CRS is typically managed using anti-inflammatory agents—one very specific way of treating these patients is by using an IL-6 inhibitor called tocilizumab, which has been approved for the treatment of rheumatoid arthritis. IL-6 levels are elevated during CRS, so by blocking this specific cytokine, you can dramatically, and very quickly, reverse the patient’s symptoms. If this treatment is not sufficient, then we do use corticosteroids—a more general way to suppress the overall immune response. And these are mostly reversible. So a patient may get sick for a time with high fever and such, but once they receive the treatment, these symptoms reverse very quickly. However, CRS can be fatal so special attention is needed to prevent and effectively manage this unique side effect.
EBO™: In your experience, are all patients equally susceptible to CRS following CAR-T treatment?
Park: We do see a range in the severity of patient responses. We have developed a grading system—mild CRS or severe CRS—to document the severity of patient response. Sometimes, we can predict how severe CRS may be in a patient, which is dictated by the patient’s disease burden. A higher disease burden means more antigens for the T cells to interact with, they get activated faster and expand to a greater degree, and more severe the CRS. So it really depends on how much disease you have, what type of T cells, and what dose of T cells is infused—which matters as well.
So there’s a host of factors that can affect the degree of CRS.
EBO™: Which types of cancers has this treatment been tried in, overall, and at MSKCC in particular?
Park: At MSKCC, we have used CAR T-cell treatment in patients with ALL, CLL, and for non-Hodgkin’s lymphoma, including diffuse large B-cell lymphoma. We also have a trial for solid tumors, specifically for mesothelioma, which is a type of lung cancer, for breast cancer, and for ovarian cancer. So these trials treating these disease types are currently enrolling patients.
We also have a pediatric ALL trial that is treating younger patients with CAR-T cells.
EBO™: CAR T-cell treatment is very expensive. When do you anticipate this treatment to be used in mainstream cancer care?
Park: Right now, the treatment is expensive, but hopefully the cost of treatment with CAR-T cells will come down. Compared with a transplant or where you need repetitive treatments with a drug such as an oral targeted drug, the advantage with CAR T-cell treatment is that 1 infusion of the drug can induce a great degree of remission. So, although the upfront cost may be high, downstream costs associated with this treatment likely decrease over time.
EBO™: This form of T-cell treatment could be considered an ‘N-of-1’ trial. Will the FDA evaluate this treatment differently, compared with the regular drug approval process?
Park: I think the FDA is viewing this therapy quite favorably because they recognize that for some of the diseases that are being studied, there currently are no good alternatives for treatment. There are some regulatory processes involved, because this treatment is categorized as a gene therapy due to the use of a retroviral or lentiviral vector for modifying the genetically engineered T cells. But the treatment has already received a breakthrough treatment designation for ALL and is close to being approved, as long as its efficacy and safety are confirmed in the ongoing large phase II clinical trials.
EBO™: Are combination trials of CAR-T cells with immune checkpoint inhibitors being planned in the near future?
Park: CAR T-cell therapy, especially in ALL, is very effective and patients can get into remission 80% to 90% of the time, which is why we are so excited about this treatment. But it’s not perfect, and not all patients benefit from it, and even after the initial respons, relapses do occur. So there’s more work needed to overcome some of these challenges, and combining CAR T-cell treatment with one of the immune checkpoint inhibitors might be one way. It could help prolong the immune response, prolong the persistence of the T cells, and hopefully prolong the duration of response.
These treatments are being evaluated at some of the centers around the country. Currently, we do not have enough data to draw conclusions on whether the combination of CAR-T cells with immune checkpoint inhibitors will be effective or whether it would result in more side effects. There are some safety mechanisms and management guidelines with these type of trials, but it’s definitely a natural next step that we are currently exploring.
Next-generation CAR-T cells are also being explored in clinical trials—these cells are made stronger even without the immune checkpoint inhibitors.
EBO™: What is your prediction about where the future lies for CAR-T cells in oncology care?
Park: We are obviously very excited about the tremendous impact of immunotherapy in cancer care. Moving from chemotherapy, which is very nonspecific, to oral targeted treatments that target specific pathways—cancer cells do become resistant to these treatments. With immunotherapy, we are not targeting any particular signaling pathway; rather we are manipulating the body’s immune system to better recognize and kill cancer cells.
So, the future, I think, is very bright and we are very close to getting this therapy approved in patients with ALL, using CD19-targeted CAR T-cells. We do have a lot of unanswered questions, such as whether treatment efficacy will remain the same with solid tumors and if not, whether we can improve efficacy with next-generation CARs or by combining the treatment with immune checkpoint inhibitors or with oral-targeted therapy.
A lot of efforts are being invested to improve the safety and efficacy of CAR-T cells, so we do expect the emergence of better and safer therapies in the future, either in combination treatments or by further modification of CAR-T cells, to hopefully lead us to a “cure” for cancer. I believe CAR-T cells is one of the ways by which we can get there.