Long-term follow-up for the development of subsequent malignancies in patients treated with genetically modified IECs

Abstract

Subsequent malignancies are well-documented complications in long-term follow-up of cancer patients. Recently, genetically modified immune effector cells (IECs) have showed benefit in hematologic malignancies and are being evaluated in clinical trials for solid tumors. While the short-term complications of IECs are well described, there is limited literature summarizing long-term follow-up, including subsequent malignancies. We retrospectively reviewed data from 340 patients treated across 27 investigator-initiated pediatric and adult clinical trials at our center. All patients received IECs genetically modified with gamma-retroviral vectors to treat relapsed and/or refractory hematologic or solid malignancies. In a cumulative 1,027 years of long-term follow-up, 13 patients (3.8%) developed another cancer with a total of 16 events (four hematologic malignancies and 12 solid tumors). The 5-year cumulative incidence of a first subsequent malignancy in the recipients of genetically modified IECs was 3.6% (95% CI: 1.8%-6.4%). For 11 of the 16 subsequent tumors, biopsies were available, and no sample was transgene positive by PCR. Replication competent retrovirus testing of peripheral blood mononuclear cells was negative in the 13 patients with subsequent malignancies tested. Rates of subsequent malignancy were low and comparable to standard chemotherapy. These results suggest that the administration of IECs genetically modified with gamma retroviral vectors does not increase the risk for subsequent malignancy.

Long-term outcomes following CAR T cell therapy: what we know so far

“…These incidences are not higher than expected given that all patients had a history of substantial chemotherapy exposure, which itself increases the risk of secondary malignancies 105,106 . The incidences of haematological malignancies, and particularly MDS, were also not higher than those expected in all trials using standard viral transduction approaches 16,23,31,59,67,89,104 . Overall, the available data provide no evidence of an increased risk of secondary malignancies with approved gammaretroviral or lentiviral CAR-delivery systems.…”

“…In the context of CAR T cell therapy, in which peripheral blood mononuclear cells undergo transduction for expression of the CAR, haematological malignancies, such as MDS, could theoretically emerge from adverse gene integration events. Data from large-cohort follow-up studies indicate an incidence of secondary malignancies after CAR infusion of 4-16% 16,31,59,89,104 . These incidences are not higher than expected given that all patients had a history of substantial chemotherapy exposure, which itself increases the risk of secondary malignancies 105,106 .…”

Emerging Challenges to Cellular Therapy of Cancer

“…Although the above data confirm the substantial promise of gene-edited allogeneic bulk T cells as the OTS platform of choice, there are risks associated with multiple genetic edits beyond the imperfect elimination of HvG. Although there is a low risk of secondary malignancies when using retroviral transduction of T cells, 7 gene editing may introduce unwanted chromosomal aberrations. Indeed, the Alpha2 trial was briefly halted because a single patient's circulating CAR T cells had a translocation involving chromosome 14 that has been associated with hematological malignancies (company press release, not published yet).…”

Long‐term survivorship care after CAR‐T cell therapy

“…Due to the potential risks of insertional oncogenesis arising from genetically modified CAR‐T cell products, 89,90 regulators have mandated long‐term monitoring for subsequent malignancies for up to 15 years after treatment 94 . Fortunately, these concerns have generally not borne out in clinical practice, as CAR‐T cell therapy has, to date, not been associated with excess risks of subsequent malignancies 23,95 . In one study of 340 patients with >1000 years of cumulative follow‐up, the incidence of new malignancies among CAR‐T cell recipients was 3.6% at 5 years, similar to the incidence observed after conventional chemotherapy and other non‐genetically modified cellular therapies 95 .…”