Chimeric antigen receptor (CAR) T-cell therapy burst upon the scene as an innovative approach to the treatment of hematologic malignancies, mainly for patients who have exhausted all other treatment options. Recently two CAR T-cell products were approved by the U.S. Food and Drug Administration (FDA), and with some 420 ongoing clinical trials, the use of this treatment is expected to expand. Despite the fact that CAR T-cell therapy is a “game-changer,” a number of problems related to its use remain to be resolved, including severe side effects such as cytokine-release syndrome and neurologic reactions; nonresponses and relapses in a sizable proportion of patients; and a high price tag, with an estimated cost of $475,000, thereby limiting the widespread use of this promising tool.Error loading Partial View script (file: ~/Views/MacroPartials/TAP Article Portrait Widget.cshtml)
At the recent Society for Immunotherapy of Cancer (SITC) Annual Meeting, a special session was devoted to new approaches in designing CAR T-cell therapy and other potential applications. The ASCO Post spoke with session Co-Chair, Marcela V. Maus, MD, PhD, who heads an immunotherapy lab at Massachusetts General Hospital, Boston, about where the field appears to be heading.
Recently two different CD19 CAR T-cell products have gained FDA approval. What are they?
Tisagenlecleucel (Kymriah) was the first CAR T-cell product to be approved, and it is used for the treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL). A few months later, axicabtagene ciloleucel (Yescarta) was approved for the treatment of adult relapsed/refractory diffuse large B-cell lymphoma (DLBCL) for which at least two prior therapies have failed.
What are the success rates with these approved therapies?
In the global ELIANA trial, the 3-month complete remission rate was 83% with tisagenlecleucel, and the probability of survival was 89% at 6 months.1 The primary analysis of the ZUMA-1 trial showed an overall response rate of 82% and a complete response rate of 54% after a single infusion of the therapy.2 At a median follow-up of 8.7 months, 44% were in ongoing response. The 6-month complete response rate was 47%.
Thus, the frequency of responses was somewhat more dramatic in pediatric B-ALL than in adult relapsed/refractory DLBCL, but they are impressive in both diseases.
What would you say are the major challenges related to the use of CAR T-cell therapy for leukemias and lymphomas?
Cytokine-release syndrome continues to be a problem. In the ELIANA trial, 47% of patients had grade 3 or 4 cytokine-release syndrome, and in ZUMA-1, 70 out of 111 patients had all-grade cytokine-release syndrome or neurologic toxicity. We need better education on how to administer this therapy and manage side effects.
We need better education on how to administer this therapy and manage side effects. We also need to streamline the logistics of delivering therapy. Negotiating with payers will not always be a smooth process.— Marcela V. Maus, MD, PhD
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We also need to streamline the logistics of delivering therapy. Negotiating with payers will not always be a smooth process. CAR T-cell therapy has a high price tag, and it differs from other approved therapies in that it often requires hospitalization.
CAR T-cell therapy is also being studied for the treatment of solid tumors. What are the obstacles for using this approach in that setting?
Research on CAR T-cell therapy for solid tumors is still early. Thus far, response rates have been less dramatic than in hematologic malignancies. It’s unlikely that it will be approved for the treatment of solid tumors any time in the next 2 years. To make progress in this area, we need better science to identify good targets, to develop strategies for getting past a hostile tumor environment, and to find better ways to protect T cells from immune suppression within the tumor.
What are some of the current directions in CAR T-cell research? What do specific studies presented at the SITC Annual Meeting show?
Martin Pulé, PhD, of University College London, presented early work on using a different CAR strategy to treat multiple myeloma.3 In this case, the CAR is based on a natural ligand, not an antibody, and it would recognize two different antigens: BCMA and TACI. Dr. Pulé also discussed the use of CAR T cells for the treatment of T-cell lymphomas, a collection of relatively rare diseases that are often neglected by researchers. His group is trying to figure out which antigens to target, because in T-cell lymphomas, the same antigens are expressed on normal and tumor cells. One of the targets being studied is TRBC, which comes in two “flavors” in normal T cells, but because tumors are clonal, they come in only one flavor.
For hematologic malignancies, research is needed to identify new targets and new combinations…. For solid tumors, research is needed to overcome obstacles in the tumor microenvironment that block T-cell function.— Marcela V. Maus, MD, PhD
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Crystal L. Mackall, MD, of Stanford University, Palo Alto, California, discussed studies of CD22 CAR T-cell therapy in pediatric leukemias.4 The studies showed that CD22 was not as good a target as CD19, because it is not as widely expressed on leukemia cells, but it can still work. Dr. Mackall suggested that a better approach might be to use a bispecific CAR T-cell product aimed at both CD19 and CD22. Thus far, three patients have been treated at her institution with the bispecific CAR T cells. Dr. Mackall also discussed novel CAR T cells directed toward GD2, which have potential therapeutic use in neuroblastoma.
Steven Gottschalk, MD, of St. Jude Children’s Research Hospital, Memphis, presented early data on the use of CAR T cells in solid tumors.5 Some responses have been seen in early studies of brain tumors and sarcomas. Although most of the responses were not dramatic, there are early hints that CAR T-cell therapies may offer benefit in solid tumors.
Jennifer Brogdon, PhD, of Novartis Institutes for Biomedical Research in Cambridge, Massachusetts, described early studies of a new CAR T-cell product—CART-EGFRvIII—in recurrent glioblastoma.6 EGFR variant III is expressed in about 30% of glioblastomas. Some activity was seen with the new product, but all 10 patients who received it eventually had disease progression. Dr. Brogdon said it remains challenging to treat recurrent glioblastoma, and more research will be done to see if a combination strategy will have better results. She also discussed a CAR T-cell product directed to mesothelin, which could be used for mesothelioma, ovarian cancer, or pancreatic cancer.
What are the future directions of research for CAR T-cell therapy in hematologic and solid tumors?
For hematologic malignancies, research is needed to identify new targets and new combinations. There are currently 420 clinical trials of CAR T-cell therapy and potentially thousands of combinations to study. The challenge will be to select better preclinical models to identify potential combinations.
For solid tumors, research is needed to identify better targets or salvage imperfect targets, as well as to overcome obstacles in the tumor microenvironment that block T-cell function. ■
DISCLOSURE: Dr. Maus has received consulting fees from Novartis, Juno, Kite, and Bluebird Bio. She is also an inventor on patents held by the University of Pennsylvania, some of which have been licensed to Novartis.
1. Buechner J, Grupp SA, Maude SL, et al: Global registration trial of efficacy and safety of CTL019 in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia: Update to the interim analysis. 2017 European Hematology Association Annual Congress. Abstract S476. Presented June 24, 2017.
2. Locke FL, Neelapu SS, Bartlett NL, et al: Clinical and biologic covariates of outcomes in ZUMA-1: A pivotal trial of axicabtagene ciloleucel in patients with refractory aggressive non-Hodgkin lymphoma. 2017 ASCO Annual Meeting. Abstract 7512. Presented June 5, 2017.
3. Pulé M: CAR T cells: Smarter targeting and smarter targets. 2017 Society for Immunotherapy of Cancer Annual Meeting. Session 300. Presented November 12, 2017.
4. Mackall CL: Updates in CAR T cells. 2017 Society for Immunotherapy of Cancer Annual Meeting. Session 300. Presented November 12, 2017.
5. Gottschalk S: Genetically modified T cells for solid tumors. 2017 Society for Immunotherapy of Cancer Annual Meeting. Session 300. Presented November 12, 2017.
6. Brogdon J: Late-breaking: CD19 CAR enter the mainstream. 2017 Society for Immunotherapy of Cancer Annual Meeting. Session 300. Presented November 12, 2017.
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