Barriers to Immune Effector Cell Therapy: Rapid Disease Progression, Concern for Toxicity, and Lack of Appropriate Trials Drive Non-Receipt after Referral at a Large Academic Center

Introduction: Immune effector cell (IEC) therapy, in the form of Chimeric Antigen Receptor (CAR) T cell and other immune cells has transformed the treatment of hematologic malignancies. Autologous cellular therapy is complex, lengthy, and expensive and poses barriers even after a patient has been referred for IEC therapy. We sought to determine the causes of non-receipt of IEC therapy among patients referred to the cellular therapy service (CTS) of a large academic center.

Methods: We conducted a retrospective study among all patients with a hematologic malignancy for whom a referral for the CTS was entered in the electronic medical record between 9/2021 and 7/2023 in a single large academic cancer center with a dedicated CTS. Demographics, disease characteristics, laboratory values, cell infusion, and reasons for non-receipt were extracted from the medical record. We sought additional input from clinical trials nurses, CTS coordinators, and primary attending physicians to ascertain the reasons for non-receipt. Social Vulnerability Index (SVI) was assigned to patients according to the US Centers for Disease Control based on their home address ZIP code.

Results: During the study period, 400 patients were referred to CTS; 224 (56%) received an IEC infusion and 176 (44%) did not. Of 197 patients with lymphoma, 64% received an infusion compared to 48% of 176 myeloma patients and 48% of 27 patients with other diagnoses (p = 0.004). Among 34 Black patients, only 35% received an infusion, compared to 60% of 294 white patients and 59% of 44 patients identifying with another race (p = 0.023). In a logistic regression, after adjustment for diagnosis, Black patients were less likely to receive IEC than white patients (Hazard ratio 0.4, 95% Confidence Interval 0.18-0.84, p = 0.018). Age, sex, Hispanic ethnicity, language, SVI, ECOG performance status > 1, and year of referral were not associated with receipt of infusion. Laboratory values at time of CTS referral of white blood cell count, platelet count, absolute neutrophil count, absolute lymphocyte count, lactate dehydrogenase, and bilirubin were not significantly associated with receipt. Patients who did not receive an infusion had slightly lower hemoglobin values than those who did (11.2 vs. 11.6g/dL, p = 0.023).

Among the 176 patients who did not receive IEC therapy, the predominant reason was rapid disease progression, affecting 37 patients (21%). Other significant reasons included the unavailability of appropriate approved IEC therapy or clinical trials for 34 patients (19%), and concerns about IEC-related toxicity in 32 patients (18%) (15 patients deemed not to be good candidates for IEC due to comorbidities by their physician, 13 patients had toxicity concerns, and 4 unknown). 30 patients (17%) did not require IEC therapy at the time of referral due to no active disease. Logistical issues were a factor for 28 patients (16%) (14 patients preferred not to relocate, 7 had no apheresis slot available, 1 had no available caregiver, and 6 had other logistical issues). Additionally, concerns about efficacy affected 9 patients (5%) (7 physician concerns, 1 patient concern, and 1 unknown), and cell manufacturing failure was the reason for 4 patients (2%). We were unable to ascertain the reason for non-receipt in 2 (1.1%) patients.

When comparing the reasons for non-receipt of IEC across disease entities, the following was observed: Rapid disease progression affected 27% of lymphoma and 16% of myeloma patients, logistical concerns affected 7% of lymphoma and 24% of myeloma patients, and lack of available trial or commercial option affected 14% of lymphoma and 21% of myeloma patients.

Conclusions: In a large academic cancer center with a dedicated CTS, almost half of the referred patients did not receive an IEC infusion. Rapid disease progression, concern for toxicity, and lack of appropriate IEC options were the most common barriers. Thus, the development of safer IECs with shorter manufacturing times (including off-the-shelf, allogeneic IECs) may increase access and potential benefit of this technology. Education of patients and physicians could also help enable earlier referral for IEC consideration, which may have been impactful for patients who were unable to receive IEC due to rapid disease progression. The racial disparity in IEC receipt should be further investigated.