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This module features a selection of questions asked by participants during a 2019 local live meeting series focused on best practices in CAR T-cell therapy in the community setting, with responses provided by members of the program faculty.
CAR T-Cell Products and Preparation
What are the currently approved CAR T-cell products and what are their indications?
As of February 2020, the CD19-targeted CAR T-cell therapies axicabtagene ciloleucel and tisagenlecleucel are both approved for use in the United States. Tisagenlecleucel is approved for patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse. Tisagenlecleucel is also approved for adults with relapsed/refractory (R/R) large B-cell lymphoma after ≥ 2 lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from follicular lymphoma, and high-grade B-cell lymphoma. Axicabtagene ciloleucel is also approved for adults with R/R large B-cell lymphoma after ≥ 2 lines of systemic therapy, including DLBCL not otherwise specified, DLBCL arising from follicular lymphoma, primary mediastinal large B-cell lymphoma, and high-grade B-cell lymphoma.
What is the time interval between administration of lymphodepleting chemotherapy and injection of CAR T-cells?
It is recommended that there be an interval of 2 days in between completion of lymphodepleting chemotherapy and injection of CAR T-cells. In practice, varied complications (eg, fever) may extend this interval up to 2 weeks.
How do manufacturers assess the quality of the CAR T cells during and after the production process?
In general, cells are monitored throughout the production process and tested for anti-tumor specificity, purity, safety, and viability. The potency of CAR T cells is typically determined through in vitro cytotoxic T-lymphocyte assay or interferon-sigma secretion.[2,3] Different companies have different assessment protocols for their CAR T-cell products.
CAR T-Cell Therapy: Efficacy and Optimal Use
Are there any studies that compare CAR T-cell therapies with standard of care?
Currently, there are no data from studies comparing CAR T-cell therapy with standard care; however, there are currently several ongoing randomized phase III trials assessing this, including:
Of note, a recent retrospective analysis compared data from the SCHOLAR-1 trial (a retrospective analysis of 2 phase III trials and 2 observational cohorts in which patients received non–CAR T-cell treatment for R/R DLBCL) and the ZUMA-1 trial (a single-arm, open-label phase II trial assessing axicabtagene ciloleucel for patients with refractory large B-cell lymphoma).[4-6] The SCHOLAR-1 study demonstrated poor outcomes for patients with R/R DLBCL, with an ORR of 26% and a CR of 8%. The ZUMA-1 trial demonstrated an ORR and CR of 82% and 54%, respectively, and a 6-month OS rate of 80%. A comparative analysis of outcomes from ZUMA-1 and SCHOLAR-1 revealed that the overall risk of death in ZUMA-1 was reduced by 77% relative to SCHOLAR-1 (P < .0001).
Would you consider CAR T-cell therapy rather than transplant in a patient with DLBCL who is demonstrating a PR rather than a CR to salvage chemotherapy?
There is an ongoing debate about CAR T-cell therapy in this setting, and randomized trials will be quite helpful to answer this question. Patients with a VGPR may have the option of autologous transplant, but they will certainly be eligible for CAR T-cell therapy as well. There are data to support both options. For those patients, it is important to weigh the pros and cons of each therapy. For example, a patient who has received CAR T-cell therapy will receive less overall chemotherapy compared with an autologous transplant. On the other hand, there are more long-term data for autologous transplant as opposed to approximately 2 or 3 years of data with the CAR T-cell therapy. These are the types of discussions that should occur with the patient.
Is there any difference between responses to CAR T-cell therapy in those who’ve undergone an autologous transplant vs those with refractory disease who have not had an autologous transplant?
There are both clinical trial and real-world data on this subject, and so far there appears to be no notable difference. Similar responses have been observed among primary refractory patients, those who were refractory to previous lines of therapy, and those who have received a transplant.[5,7,8]
Is there any indication that repeat CAR T-cell therapy at 2-3 years following initial treatment would be a viable option for relapsing patients?
There are limited data on this because most relapses following CAR T-cell therapy happen within the first 6 or 8 months. It should be noted that repeat CAR T-cell therapy is only possible if there are leftover cells following the first infusion. In addition, reinfusion is not approved by most insurance providers, so out-of-pocket cost to remanufacture the cells would be considerable. Cell production typically ends after 2 weeks, which may produce enough cells for 2 -4 doses, depending on patient weight. The shelf life of these cells is several years, which is what made the clinical trials possible. So technically, repeat CAR T-cell therapy is possible, but its use may be limited by practical considerations.
Managing CAR T-Cell–Associated Toxicities
When is it appropriate to provide a second dose of tocilizumab for cytokine-release syndrome associated with CAR T-cell therapy?
Every institution and clinician has a different protocol for additional dosing of tocilizumab for cytokine-release syndrome associated with CAR T-cell therapy. At my institution (Dr. Jae Park), we typically wait 6-8 hours after the first infusion of tocilizumab. Tocilizumab is a 1-hour infusion, so a cytokine-release syndrome response (eg, normalization of body temperature and heart rate) is generally expected within 2 or 3 hours. But if patients fail to respond within 6-8 hours, I provide a second dose of tocilizumab. I will not give more than 2 doses, because I have found that patients are unlikely to respond to a third dose (although some institutions will provide 3 or more doses).
How effective is CAR T-cell therapy for multiple myeloma (MM)?
There are currently multiple trials evaluating CAR T-cell therapy for MM. Of note, results from a phase I trial of the investigational CAR T-cell agent idecabtagene vicleucel revealed a favorable safety and efficacy profile in heavily pretreated (≥ 3 previous lines of therapy) MM patients. The response rates in this study were 85% for ORR and 45% for CR. This agent was recently granted a breakthrough therapy designation by the FDA.
Are any CAR T-cell therapies being used in solid tumors?
Yes; current trials of CAR T-cell therapy in solid tumors include a phase I trial of prostate-specific membrane antigen (PSMA)–targeted CAR T-cells for metastatic castrate-resistant prostate cancer (mCRPC, NCT01140373) and a phase I trial of dual PSMA-specific/TGFβ-resistant, CAR-modified autologous T-cells (CART-PSMA-TGFβRDN cells) in mCRPC patients (NCT03089203).
What role do immune checkpoint inhibitors play in the area of CAR T-cell therapy?
Modifying the immunosuppressive action of the tumor microenvironment with immune checkpoint inhibitors is an appealing strategy to pair with CAR T-cell therapy. Clinical trial data suggest that combining immune checkpoint inhibitors with CAR T-cell therapy enhances the persistence of CAR T-cells, leading to improved outcomes. This strategy is occasionally used following relapse of CAR T-cell therapy, but the data are far from conclusive. Future trials should clarify the utility of checkpoint inhibitors in this setting.