Currently only approved for the treatment of B-cell malignancies, CAR-T cell therapy is a relatively new treatment option that researchers are learning more about each day, according to Amelia Langston, MD.
Langston, a professor and Executive Vice Chair of the Department of hematology and medical oncology at the Winship Cancer Institute of Emory University, recently presented a session on CAR-T cell therapy at CURE®’s Educated Patient® Leukemia & Lymphoma Summit, touching on not just how the treatment has evolved, but where it could be going in the near future.
CAR-T Cell Therapy 101
Langston began by defining one of the major problems that researchers are trying to solve by utilizing CAR-T cell therapy: making immunotherapy a reality for more patients with blood cancer. There are a few methods that are currently in use, including allogeneic stem cell transplantation, monoclonal antibody therapy, and checkpoint inhibitors – drugs that call upon a number of natural cellular immune responses.
At its core, the main concept of novel therapeutics is to bring the immune cells and the tumor cells together in a way that activates the immune cells to kill those cells that carry a specific target or targets. The goal is to also eliminate some of the complexities of the T-cell immune response and, according to Langston, “potentially recruit other immune players into the mix.”
The process of CAR-T cell therapy begins with T cells that are collected from a patient, Langston explained, and then manipulated in a laboratory. “We then introduce a genetically engineered chimeric antigen receptor (CAR) construct that confers specificity for an antigen on the surface of the tumor cell. And that results in killing of the tumor.”
It is worth noting, Langston said, that the manufacturing of these CAR-T cells is not trivial. Once the T cells are extracted, modified, and reproduced in large quantities, the patient then needs to be prepared with what doctors call lymphodepleting chemotherapy. This essentially makes room in the in the patient’s immune system for the new T cells to get into the body and expand. After that’s done, the T cells are delivered to the patient, where they expand inside the patient and get to work.
The Success of CD19-Targeted Cells
The first target that has been successfully applied to CAR-T cell therapy is a molecule called CD19, Langston went on to explain. This is a very attractive target because it corresponds to many of the different B-cell malignancies, with three different options currently approved by the FDA:
- Kymriah (tisagenlecleucel) – approved for patients up to 25 years old with B-cell precursor acute lymphoblastic leukemia (ALL)that is refractory or in second or later relapse, as well as adult patients with relapsed or refractory large B-cell lymphomawho have undergonetwo or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
- Yescarta (axicabtagene ciloleucel) – approved for adult patients with relapsed or refractory large B-cell lymphomawho have received two or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
- Tecartus (brexucabtagene autoleucel) – granted an accelerated approval for the treatment of relapsed or refractory mantle cell lymphoma in July 2020.
While it is an attractive option given its efficacy, CAR-T cell therapy comes with significant and unique toxicities, according to Langston – namely, cytokine release syndrome.
“The cells divide very rapidly in the patient, and they create a sort of a cytokine storm as a consequence of that rapid division,” she said. “This so-called cytokine release syndrome is characterized by high fevers, hypotension, diffuse capillary leak and swelling, and is associated with a lot of inflammatory markers. And if this complication is not identified quickly and managed appropriately, this is an absolutely life-threatening complication.” The bright spot in this potential side effect is that effective interventions to help manage it do exist, mainly in the form of Actemra (tocilizumab).
Neurologic toxicities can also arise as a result of CAR-T cell therapy, and can also be life-threatening. “Patients could have anything from a little bit of trouble with their memory, all the way to seizures and brain swelling and even death,” Langston said. However, she did note, this is a reversible complication if it is identified and treated very quickly.
A third issue that can occur is B-cell aplasia, where the manufactured CAR T-cells attack normal B-cells that also express CD19, putting patients at higher risk of developing infections. Like the other toxicities related to CAR-T cell therapy, this condition can be treated as well, with intravenous immunoglobulin replacement therapy.
The Challenging Road Beyond Blood Cancers
Citing CAR-T cell therapy success stories like that of Emily Whitehead, Langston concluded with a look at not just how this treatment can be refined and made more effective for patients, but what impact it could have on malignancies outside of the blood cancer space.
“I think one of the most important areas (we are looking at) is how do we make the CAR-T cell concept work better?” Langston asked. “Can we add other immune modulators and stimulants into the mix to try to enhance persistence of those CAR-T cells? What about the fact that we have patients with T-cells that are really pretty beaten up from their prior therapies? Can we rejuvenate their T-cells before they are transduced? Or after transduction for that matter, in order to make the CAR-T cells more robust and more powerful? Can we develop new CAR constructs that will enhance the activity without maximizing toxicity?”
When it comes to solid tumors, Langston concluded, her own institution is one of many that is currently investigating the possibilities. “We have an ongoing study (at Emory) in lung cancer, we have another study in head neck cancer, and we’re beginning to get into breast cancer as well,” she said.
While it’s challenging to identify targets in these cancers, Langston said, there is hope. “It becomes more challenging when we look at some of the solid cancers, but there’s a lot of promising data in early phase studies to suggest that this will be possible in the future.”
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