Abstract: The availability of adoptive cell therapies allows clinicians to genetically reprogram patients’ own immune cells to find and attack cancer cells throughout the body. Chimeric antigen receptor (CAR) T-cell therapy—a type of adoptive cell immunotherapy—has led to remarkable patient outcomes and has the potential to transform cancer treatment. It has started as an exclusively inpatient procedure but is evolving into the outpatient care arena. However, before cellular therapies become standard outpatient procedures, many critical issues will need to be addressed, including coordination of care, availability of specific resources, education of patients and caregivers, and toxicity management—both clinical and financial toxicity.
Acknowledgments: Thanks to the team at The US Oncology Network and McKesson, including Dr Marcus Neubauer, Jill Maddux, and Sharon Munroe.
Chimeric antigen receptor (CAR) T-cell therapy has its origins in the early work in immunotherapy, dating back to 1893 when William Coley recognized the potential of employing the immune system in treating cancer by injecting streptococcus into an inoperable sarcoma, which resulted in tumor shrinkage.1 A significant milestone in the development of adoptive cell therapies occurred in 1987 with the discovery that lymphocytes in metastatic melanoma could be transformed by IL-2.2 The use of adoptive cell therapies was first described in 1988, but the critical improvement occurred in 2002 with the introduction of an immunodepleting preparative regimen given before the adoptive transfer, resulting in improved repopulation of anti-tumor T cells.3
The development of CARs was originally considered as a conduit for transplantation in B-cell leukemias and lymphomas.4 The first successful CAR therapies were directed against B-cell hematologic malignancies, targeting the CD19 marker, which is highly specific to B-cells including those transformed to lymphoma and leukemia.5 Currently, 2 CAR T-cell products are approved by the Food and Drug Administration (FDA) in oncology: (1) tisagenlecleucel (Kymriah; Novartis) is indicated for patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse and in the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma after 2 or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma6; and (2) axicabtagene ciloleucel (Yescarta; Kite) for the treatment of adult patients with R/R large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.7 While these 2 commercially available products target B-cell malignancies, clinical trials are being conducted in other hematologic malignancies as well as solid tumors, offering promising new treatment options for patients with cancer and potentially other diseases.
CAR T-Cell Therapies Now
CAR T-cell therapy has succeeded where conventional therapies have failed. One remarkable example is the complete remission rate in pediatric and young adults with R/R B-cell ALL treated with Kymriah reported at 83% in the ELIANA trial (NCT02228096) with subsequent follow-up reporting an 81% overall remission rate.8 However, the early clinical trials leading to the current FDA-approved products were conducted in bone marrow-transplant centers to provide close monitoring of patients due to the potentially lethal toxicities of these therapies. Patients may experience an exaggerated immune response known as cytokine release syndrome (CRS), which could result in death if not diagnosed and treated promptly. Safety information for both commercially available products recommends frequent monitoring of patients post-infusion within the first week and up to 4 weeks post-infusion.6,7 Inpatient hospitalization for this period is not required unless complications occur. Some outpatient hospital departments have reported administering treatments while still permitting close monitoring of patients.
The initial clinical trials for the FDA-approved cellular therapies were conducted in academic centers, but the future administration of these therapies and the future conduct of clinical trials need not be restricted to this setting. Not all CAR T-cell products are the same and therefore have varying toxicity profiles. A true assessment of the appropriate setting for the administration of cellular therapies will be dependent upon the ability of the treatment center to meet the specific safety requirements for the safe administration and monitoring of patients.
While many oncologists view CAR T-cell therapies as a new and “potentially game-changing approach to treatment,” in one 2017 survey of 338 oncologists, 80% reported they would send some or all of their eligible patients to academic centers.9 Twenty-four percent of respondents in the same survey believed that CAR T-cell therapies could be delivered safely in a community setting, as all adoptive cell therapies are not equal and do not exhibit the same side effect or toxicity profiles. In a May 2018 survey of physicians in The US Oncology Network, approximately 70% confirmed a high-level interest in learning more about the requirements and support needed for their practice to become a CAR T-cell infusion center and/or CAR T-cell research center.10