The administration of genetically modified immune effector cells (IECs) in cancer patients does not increase the risk for subsequent malignancy, according to research published in Blood.

Treatment with genetically modified IECs has been associated with multiple short-term toxicities, especially when used in combination with lymphodepleting chemotherapy. The long-term effects of these therapies are unclear, and there remains a potential concern for subsequent malignancies in patients receiving genetically modified IECs.

Researchers conducted a retrospective study comparing the incidence of second malignancy in cancer patients treated with genetically modified IECs and cancer patients treated with unmodified IECs.

Continue Reading

There were 340 patients who had been enrolled in pediatric or adult clinical trials and received IECs genetically modified with gamma-retroviral vectors (GRVs) for the treatment of relapsed and/or refractory cancers. All of these patients had exposure to chemotherapy before enrollment in each clinical trial.

Of the 340 patients, 60.0% were adults, and 40.8% were pediatric patients. The median age was 23.5 years (range, 1 to 78 years) at enrollment. Patients had hematologic malignancies (55.3%), solid tumors (44.1%), and nonmalignant conditions (0.6%). In this cohort, 29.1% of patients had undergone an autologous hematopoietic stem cell transplant (HSCT), and 24.4% had received an allogeneic HSCT.

For comparison, researchers used a control cohort of 111 patients with Hodgkin lymphoma (45.9%) or B-cell non-Hodgkin lymphoma (54.1%) who received IECs without genetic modification before infusion. In the control cohort, 33.3% of patients underwent autologous HSCT, and 11.7% underwent allogeneic HSCT.

With a cumulative follow-up of more than 1000 years, 3.8% (13/340) of patients treated with genetically modified IECs developed a total of 16 subsequent malignancies (4 hematologic cancers and 12 solid tumors). Ten malignancies occurred within 5 years of IEC therapy, and 6 malignancies occurred more than 10 years after IEC therapy. 

In the control cohort, 3.6% (4/111) of patients developed subsequent malignancies (2 with myelodysplastic syndromes, 2 with sarcoma) at 5 years.

The 5-year cumulative incidence of a first subsequent malignancy was 3.6% in patients who received genetically modified IECs and 4.2% in the control cohort, with no significant difference between the cohorts (hazard ratio, 0.9; 95% CI, 0.3-2.9; P =.953). 

Of the 13 patients with a subsequent malignancy in the genetically modified cohort, 11 had tumor biopsies available. All tumor samples were negative for the presence of transgenes and replication-competent retrovirus by quantitative PCR analysis. 

The overall rate of subsequent malignancy in patients treated with genetically modified IECs was low and was comparable to rates observed with standard chemotherapy, according to the researchers.

They concluded that these data reinforce the safety of retroviral genetically modified IECs, as GRV-modified vectors did not significantly increase the risk of subsequent malignancies. However, the researchers added, long-term studies will be needed to determine the risk of subsequent malignancies in the transposon systems and in lentiviral IECs.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Steffin D, Muhsen IN, Hill LC, et al. Long term follow-up for the development of subsequent malignancies in patients treated with genetically modified IEs. Blood. Published online March 24, 2022. doi:10.1182/blood.2022015728