Engineered T Cells for Cancer

In this webinar, Professor Marcela Maus explains the components and technologies used in making a chimeric antigen receptor (CAR) T cell product, important considerations for efficacy, and underlying mechanisms of toxicity and resistance.

• Methods of engineering CAR T cells
• Classes of CAR T cells and their mechanisms of action
• How living drugs are used in cancer treatments
• Predicting patient responses with CAR T cell attributes
• Varying CAR T cell components to determine their clinical activity

Professor Maus begins this webinar by noting that the field of CAR T cell therapy developed rapidly in 2011, when CAR T cells targeting human CD19 were found to induce antitumor responses in several patients. Several CAR designs have been approved by the Food and Drug Administration in the past decade, while many more are undergoing development and evaluation.

Participants in CAR T cell clinical studies generally consist of patients with relapsed or refractory (r/r) disease who have not responded to multiple regimens of chemotherapy or biologic therapy. In 2017, tisagenlecleucel (tisa-cel) was first approved for pediatric r/r acute lymphoblastic leukemia (ALL) with an overall response rate (ORR) of 83%. Professor Maus notes that some of the newer CAR T cells currently in development have ORRs of higher than 90%.

“CAR T cells . . . I can’t . . . emphasize this enough, have really transformed the treatment of patients with hematologic malignancies.”

In pediatric patients with r/r ALL, chemotherapy and biologic therapy do not tend to provide a good overall survival (OS). A clinical study of clofarabine in combination with etoposide and cytoxan yielded a median OS of 2.5 months. Biologic therapy with blinatumomab improved the median OS to 7.5 months in a similar patient population, which further increased to 19.1 months following the introduction of tisa-cel.

CAR T cells are living drugs, meaning the administered dose is not the final dose to which patients are exposed. These cells undergo a very rapid expansion in the patient following infusion and will persist for months or even years. For tisa-cel, a 4-1BB-based CAR, long term persistence is important for its function. Interestingly, for brexucabtagene autoleucel (brexu-cel), a CD28-based CAR, the extent of expansion matters more than persistence in terms of its antitumor effect. The attributes and characteristics of CAR T cells strongly influence their activity and clinical profile. In fact, these attributes matter more in predicting responses than tumor genotype or prognostic biomarkers, which Professor Maus remarks is a significant paradigm shift in oncology.

Professor Maus further notes that challenges with CAR T cell therapy differ in liquid and solid tumors. For instance, challenges specific to liquid tumors include high potency, antigen escape, and a lack of persistence. An overlapping challenge in liquid and solid tumors is the identification of tumor-specific targets, although this is more difficult with solid tumors since surface target antigen identification is not part of routine clinical care as it is in patients with liquid tumors. Challenges specific to solid tumors include tumor heterogeneity, suppressive tumor microenvironments (TMEs), and a lack of bioactivity.

In Professor Maus’ group, CAR T cell therapy for liquid tumors has employed a proliferation-inducing ligand (APRIL) that binds to both B-cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI). A truncated, trimeric version of APRIL (TriPRIL) is advantageous over a BCMA-based CAR in that it avoids relapse by binding to two antigens at once, increases binding affinity, and avoids immunogenicity using a fully human protein.

For therapy of solid tumors, the Maus group evaluated the efficacy of epidermal growth factor receptor variant III (EGFRvIII)-directed CAR T cells. While CAR T cells were trafficked to the tumor and targeted the EGFRvIII antigen, there was antigen heterogeneity and an increase in the immunosuppressive TME characterized by the infiltration of regulatory T cells (Tregs). Building on this work, a T cell engaging antibody molecule (TEAM) was designed to target a second antigen, thus overcoming the heterogeneity problem and bypassing the infiltrating Tregs. The secreted TEAM could locally target wild type EGFR expressed by the tumors, rapidly clear leakage into peripheral blood, and redirect Tregs with no on-target, off-tumor toxicity.

“Not all CAR T cell products are the same, nor do they behave the same way in all malignancies.”

Professor Maus further explains that CARs are modular structures, and so a variety of binding, hinge, transmembrane, co-stimulation, and activation domains can be engineered. For molecular changes, drugs can be added to increase CAR T cell efficacy and sensitize T cells to tumors, as demonstrated by the Maus group with ibrutinib. Gene edits can also be made to change the “background” information of T cells and determine their fate.

The bioactivity of CAR T cells has been extremely impressive to date, both in terms of durability responses and toxicities that can be managed clinically. Biological advances made over the past several years have allowed for the rapid translation of CAR T cell development to clinical trials. Professor Maus remarks that the growing interest in and success of CAR T cell therapies could lead to their use as a first-choice cancer treatment in the future.