CAR T-Cell Therapy: A Healthcare Professional's Guide to KTE-C19 Studies

Emerging immunotherapies such as chimeric antigen receptor (CAR) T-cell therapies are some of the most exciting new investigational agents in oncology today. On August 30, 2017, the FDA approved Kymriah (tisagenlecleucel) the first CAR-T cell approved for certain pediatric and young adult patients with acute lymphoblastic leukemia (ALL).

Clinical trial results have been remarkable in refractory leukemias and lymphomas, leading to sustained, high rates of remission in some patients. However, treatments are not without risks.

U.S. Food and Drug Administration (FDA) reviews are in process, and a decision is expected in 2017 for hematologic malignancies such as aggressive B-cell non-Hodgkin lymphoma (NHL). Other blood cancers under research for CAR T include chronic lymphocytic leukemia (CLL). Studies are also in process for a wide array of solid tumors such as melanoma or breast cancer, and more follow-up will determine if CAR T-cell therapy is an option for these tumors.

Here, we continue this series to review clinical trials for KTE-C19, a CAR T-cell therapy now up for FDA review.

CAR T-cell therapy is a new form of immunotherapy, a type of gene therapy.

In CAR T, a patient's T cells, a form of white blood cell, are separated out and engineered to express a chimeric antigen receptor (CAR) to target the tumor antigen CD19, a protein on the cell surface of B-cell lymphomas and leukemias. The re-engineered CAR T-cell is then re-infused back into the patient and redirects the T cells to kill the cancerous cells.

For an introductory review of tumor pathophysiology and CAR T-cell mechanism of action, see these related slideshows:

• CAR-T Cell Therapy: A Healthcare Professional's Guide - Introduction: The Tumor

• CAR T-Cell Therapy: A Healthcare Professional's Guide - Mechanism of Action

Axicabtagene ciloleucel (KTE-C19) from Kite Pharma is an anti-CD19 CAR-T breakthrough therapy currently under FDA review for relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) in patients who are ineligible for autologous stem cell transplant. This product was initially developed at the National Cancer Institute (NCI). On March 31, 2017, Kite announced they had completed the rolling submission for the Biologics License Application (BLA). If FDA-approved, Kite plans to launch axicabtagene ciloleucel in 2017, and it would be the first commercially available gene therapy for non-Hodgkin lymphoma.

Kite's ZUMA-1 pivotal trial assessed treatment of aggressive refractory B-cell lymphoma with axicabtagene ciloleucel in 101 patients (including diffuse large B-cell lymphoma [cohort 1, n=77], and mediastinal B-cell lymphoma and transformed follicular lymphoma [cohort 2, n=24). After one infusion of axicabtagene ciloleucel, the primary endpoint for the combined groups was met with a statistically significant 82% objective response rate (ORR). At 6 months, the ORR was 41%, with 36% of patients still in complete response (CR). Five of the 101 patients continued to exhibit durable partial responses (PR) with minimal abnormalities in PET scans. One of these PRs converted to a CR at month nine. At 8.7 months, the median overall survival (OS) had not yet been reached, although a similar patient population from the SCHOLAR-1 study had a median OS of 6.6 months.

Axicabtagene ciloleucel (KTE-C19) was granted breakthrough therapy designation for all 3 lymphoma subsets by the FDA in 2015 as it tackles a significant unmet need - patients with aggressive B-cell lymphoma who have run out of treatment options. However, some side effects can be serious. In ZUMA-1, the most common grade 3 or higher adverse events included:

• Anemia (43%), thrombocytopenia (24%)
• Neutropenia (39%), febrile neutropenia (31%), decreased neutrophil count (32%)
• Decreased WBC count (29%), decreased lymphocyte count (20%)
• Neurologic events (28%)
• Encephalopathy (21%)
• Cytokine release syndrome, CRS (13%)

CRS is a serious, potentially fatal, side effect of any CAR-T cell therapy that results in cytokine release causing high fevers, low blood pressure, and neurologic side effects like delirium and confusion. Side effects like CRS and neurotoxicity have been managed with the interleukin (IL-6) inhibitor tocilizumab (Actemra). On August 30, 2017 the FDA approved Genentech's Actemra as treatment for CAR-T associated CRS.

Three deaths were originally reported; 2 deemed related to therapy. One case was reported as hemophagocytic lymphohistiocytosis, where the immune system damages the patient’s own tissues and organs, and one cardiac arrest in the setting of CRS. In May 2017, OncLive reported on a death due to cerebral edema in a patient with explosive disease in a Phase 2 safety study of ZUMA-1.

In the ZUMA-2 trial, Kite Pharma is also evaluating the treatment of relapsed/refractory mantle cell lymphoma (MCL) with KTE-C19. MCL is an aggressive B-cell lymphoma comprising roughly 6% of non-Hodgkin lymphomas.

In the ongoing ZUMA-2, the main objective is to assess safety and efficacy of KTE-C19, as measured by overall response rate. Secondary endpoints include duration of response, progression-free survival, overall survival, pharmacokinetics, pharmacodynamics, and predictive biomarker analyses. The study is planned at approximately 25 sites in the United States and European Union.

• If patients or practitioners would like more details about ongoing clinical trials, information can be found at the National Cancer Institute's clinical trials website.

Axicabtagene ciloleucel (KTE-C19) is also being investigated in the ZUMA-3 and ZUMA-4 trials for treatment of relapsed/refractory acute lymphoblastic leukemia (r/r ALL) in adult and pediatric patients.

In the Phase 1 trials, 13 patients with r/r ALL were treated with KTE-C19; eleven patients were evaluable for response. At the time of the preliminary analysis, 82% of patients (9 out of 11) achieved complete remission or complete remission with incomplete or partial hematological recovery. All responders (100%) tested negative for minimal residual disease (MRD), which is correlated with risk of disease relapse in ALL.

Adverse events grade 3 or higher included cytokine release syndrome (5 of 13 patients, 38%) and neurological events (5 of 13 patients, 38%). There were two deaths: one patient in ZUMA-3 died from KTE-C19 related cytokine release syndrome (CRS) and one patient in ZUMA-4 died from an unrelated fungal infection. Larger Phase 2 studies in r/r ALL will be ongoing in 2017.

CAR T-cell therapy positive response rates in aggressive leukemias and lymphomas are impressive, but relapse or progression does occur in some patients after initial response. Is there a way to address this?

The ZUMA-6 studies are now underway to evaluate the effectiveness of a combined immune checkpoint inhibitor (anti-PD-L1) and CAR T-cell regimen. Kite Pharma is investigating Genentech's approved PD-L1 drug atezolizumab (Tecentriq) alongside KTE-C19 in patients with refractory, diffuse large B-cell lymphoma (DBCL). This research will determine if the combination can cause a cohesive effect and extend KTE-C19’s activity.

According to a Feb. 2017 report in Hematology and Oncology from Dr. Sattva S. Neelapu at MD Anderson Cancer Center in Houston, clinical trials are looking at whether progression or loss of effectiveness occurs when T cells become exhausted after interacting with the tumor. If indeed this is the case, researchers are also evaluating whether immune checkpoint blockade can reactivate the exhausted T cells.