Jae H. Park, MD
Chimeric antigen receptor (CAR)-modified T-cell therapies have demonstrated durable complete responses (CRs), the majority of which are minimal residual disease (MRD)-negative, for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). However, several questions still remain regarding their optimal use and applicability outside of ALL, according to Jae H. Park, MD, at the 2016 International Congress on Hematologic Malignancies.
“What we have learned from ALL is that they are very effective at getting to complete remissions, and the responses are very deep. Durable responses have been observe in a subset of patients who did not get subsequent allogeneic transplant,” said Park, Leukemia Service at Memorial Sloan Kettering Cancer Center. “There are a lot of questions, as we move forward, such as the role of the tumor microenvironment, and whether this can be applied outside of ALL.”
A CAR therapy consists of the binding domain from an antibody connected to the signaling domain of a T cell. The process for the therapy involves the insertion of a CAR gene subclone that recognizes a tumor antigen into a viral vector, which is transduced and expanded ex vivo
in T cells and then administered to the patient. The resulting therapy has the specificity of an antibody with the killing capacity of a T cell, Park said.
At this point, clinical trials have primarily focused on CD19 and other markers on B-cell malignancies. CD19 was explored first, since it is not expressed in hematopoietic stem cells and is overexpressed in B-cell lymphoma, leukemia, and occasionally in multiple myeloma.
“With CD19, because it's not expressed on stems cells, we are only targeting mature cells. However, because the antigen is also expressed in normal B-cells, we do cause B-cell aplasia,” said Park. “We also have CARs planned for CD22 and CD20, which are other common B-cell antigens.”
CAR-modified T-cell therapies have undergone several changes since they were initially introduced, and continue to be improved and modified. They offer the advantage of having HLA-independent antigen recognition, which provides broad application across both solid and blood cancers. These therapies are also active in both CD4+ and CD8+ T cells, with a minimal risk of graft-versus-host disease.
“This is potentially a living drug. They can survive within the body and provide immunity against cancer,” said Park. “Because this is a genetic therapy, the door is open to more genetic modifications and better versions of the T-cells as the years go on. In the future, we may even be able to accomplish better results, and in solid tumors as well.”
Findings in Acute Lymphoblastic Leukemia
Historically, patients with ALL who are in their first relapsed have a 5-year overall survival (OS) of 7% to 8% and a 2-year OS of 11%. Additionally, in clinical trials studying conventional chemotherapy, the CR rates ranged between 18% and 45% for patients with relapsed/refractory ALL. These poor outcomes emphasize the need for novel therapies, said Park.
In phase I trials exploring CAR T-cell therapies, leukapheresis is conducted upfront to collect T cells for modification followed by chemotherapy, to keep the disease in check. After the T-cell production period, which takes 2 to 3 weeks, a bone marrow biopsy is conducted to assess the response to chemotherapy. After this step, the patient will receive a conditioning chemotherapy followed by an infusion of the T-cell therapy.
“The conditioning therapy, what we think it is doing, is lymphodepletion. It simply is creating a space for these T-cells to get in there and expand. In order for this T-cell therapy to be successful, you do need T-cell activation and expansion,” said Park.
As early phase results have been analyzed, a number of modifications were made to this study design. Initially, the conditioning chemotherapy was cyclophosphamide alone; however, fludarabine has now been added, Park noted. Additionally, the second infusion of the CAR T-cell therapy is customized, based on the number of blast cells present, to address toxicity concerns.
“The dosing adjustments here are counterintuitive, in a way, the more disease you have, you actually need less T-cells, since disease really means antigen load,” said Park. “The more antigen there is, the T-cells will engage and expand a lot quicker and faster, and as they do that, that is when the toxicity comes in.”
CAR T-cells in Action
As an example of the outcomes seen with CAR T-cell therapy, Park presented data from a 46-patient phase I study that was conducted by Memorial Sloan Kettering Cancer Center (NCT01044069). In this example, the median age of patients was 45 years and the median number of prior therapies was 3.1