CAR T Cell Immunotherapy Promising in Refractory Leukemia
CAR T cells expand dramatically (blue) in the peripheral blood of patients and coincide with elimination of CD19+ normal B cells (green) and leukemic blasts (red).
B-cell acute lymphoblastic leukemia (B-ALL) is a common childhood malignancy that also affects young adults. Although current treatments have significant toxicities, children with chemotherapy susceptible subtypes have high survival rates. However, less than 10 percent of children and young adults with newly-diagnosed or recurrent B-ALL that is insensitive to therapy survive, and this rate has not budged in the last 20 years.
Therapies that harness the power of the immune system are a more recent addition to the anticancer arsenal. One such therapy genetically reprograms a patient’s own T cells to express a chimeric antigen receptor (CAR), which includes a recognition sequence for a particular protein, usually from an antibody, attached to signaling domains that induce T cell activation, to eliminate cells that express the targeted protein. CAR T cells that recognize CD19, a protein expressed on the surface of nearly all B cells, have been reported to have anticancer activity in small case studies of patients with several B cell malignancies, including B-ALL. A team of researchers led by Crystal Mackall, M.D., Chief of CCR’s Pediatric Oncology Branch (POB), and Daniel W. Lee, M.D., also of POB, conducted a Phase I clinical trial of CD19-directed CAR T cells to assess treatment feasibility, the maximum dose patients could tolerate, and outcomes in a larger population of patients treated with a uniform protocol.
Between July 2012 and June 2014, 21 patients, ranging in age from five to 27 years old, enrolled in the trial. Twenty had refractory B-ALL, and one had recurrent B cell non-Hodgkin lymphoma. All patients had received multiple prior treatment regimens, including allogeneic hematopoietic stem cell transplant (HSCT) in eight of the patients. Once enrolled, patients underwent T cell harvesting, and the investigators generated CD19 CAR T cells using a rapid, 11-day manufacturing process. Following an immune cell depleting regimen consisting of fludarabine and cyclophosphamide, patients received a single infusion of CD19 CAR T cells. The regimen had a 90 percent feasibility rate with 19 patients receiving their prescribed dose. The other two patients received lower doses because sufficient numbers of cells could not be generated. All patients received infusions of fresh cells except one who received cryopreserved cells to allow him to recover from an infection.
Based on results from the first eight patients who received their prescribed dose, the investigators established the maximum tolerated dose (MTD) as 1x106 CD19 CAR T cells per kilogram, and the next 11 patients received this dose. Using intent-to-treat analysis, two-thirds of patients experienced a complete response to CAR T cell therapy, with 12 of the 20 B-ALL patients (60 percent) having no residual disease, including one patient who received a lower than prescribed dose of cells. Six of the responding patients had never previously entered a no-detectable-disease remission despite many rounds of intensive chemotherapy. The overall survival at a median follow up of 10 months was 52 percent, and the leukemia-free survival in patients with no detectable disease response was 79 percent. The therapy also eliminated leukemia from the central nervous systems of two patients. All responding patients had B-ALL, and this response rate in refractory pediatric ALL is higher than that of the most-recently Food and Drug Administration approved agent.
Ten of the patients with no residual disease subsequently underwent HSCT and remain disease free with no unexpected transplant-related toxicities. Two patients with no residual disease were not eligible for HSCT and relapsed with CD19-negative leukemia in less than six months. Three other patients received a second dose of CD19 CAR T cells, but none experienced a significant response.
All side effects from CAR T cell therapy were reversible. The most severe was Grade 4 cytokine release syndrome (CRS) in three patients caused by the release of large amounts of cytokines into the blood stream that can cause high fevers or dramatic drops in blood pressure. Overall, 16 patients experienced CRS of any grade. CRS was managed with supportive care alone in 12 patients; with supportive care plus the anti-interleukin-6 (IL-6) receptor inhibitor tocilizumab in two patients; and with supportive care, tocilizumab, and corticosteroids in two patients. Patients with a higher disease burden had more severe CRS. Other common side effects included fever, low potassium level, and neutropenia. There was no evidence of graft-versus-host disease in patients who had undergone HSCT prior to enrolling in the trial.
The researchers also analyzed blood samples taken from patients throughout the trial to observe the effects of treatment on immune and cancer cells and cytokine levels. In the majority of responding patients, the investigators observed no circulating B cells after the chemotherapy and CAR T cell treatments, but B cell progenitors generally recovered about a month after treatment. They also observed dramatic CAR T cell expansion that coincided with a reduction in leukemia cells (see the figure). Likewise, CAR T cell expansion positively correlated with patient response and toxicity.
The researchers also found that Grade 3 or 4 CRS associated with higher levels of IL-6, interferon-γ, and C-reactive protein. Finally, the investigators uncovered patient immune responses to the CAR T cells that may diminish the cells’ persistence in the body. However, patient outcomes suggest that long-term persistence is not necessary for clinical benefit.
Taken together, these results demonstrate that CD19-targeted CAR T cell immunotherapy is an effective bridge to HSCT in chemotherapy-resistant B-ALL, potentially increasing survival in a patient population that has not improved in decades.Summary Posted: 11/2014
Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, Rosenberg SA, Wayne AS, Mackall CL. T Cells Expressing CD19 Chimeric Antigen Receptors for Acute Lymphoblastic Leukemia in Children and Young Adults: a Phase 1 Dose-escalation Trial. Lancet. October 13, 2014 PubMed Link