Malignancy risk from genetically modified immune effector cells, p53 immunohistochemistry as a new tool in AML, and phenotypic escape from CD19-directed immunotherapies.
In this week’s episode we’ll learn more about the risk of subsequent malignancies in patients treated with genetically modified immune effector cells, discuss how p53 immunohistochemistry can be a global readout for TP53 alterations in AML, and uncover the role of CD19-negative CD22-positive B-cell progenitors in immune escape from CD19-directed therapies. .
Long-term follow-up for the development of subsequent malignancies in patients treated with genetically modified IECs
Steffin and colleagues report on the development of secondary malignancies in 340 patients treated with genetically modified immune effector cells (IECs) from 27 different clinical trials over more than 1000 patient-years of follow-up. Secondary malignancy was seen in 16 patients (3.6%), comparable to what is seen with standard chemotherapy alone. Reassuringly, in 11 available biopsies, none carried the transgene, suggesting that IECs modified with gammaretroviral vectors do not increase the risk of secondary malignancy.
Anti-CCR9 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia
Maciocia and colleagues identify CCR9 as an antigen expressed on >85% of relapsed T-ALL and on <5% of normal T cells, demonstrating in cell lines and patient-derived xenografts that CAR-T cells targeting CCR9 have potent anti-leukemic activity without any evidence of fratricide.
CD34+CD19−CD22+ B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies
Bueno et al identify CD34+CD19−CD22+ cells in patients at diagnosis and relapse; they further show that CD22 expression precedes CD19 expression and that this population harbors the same genetic abnormalities of the B-ALL clone. They propose that this may represent a progenitor population that can give rise to B-ALL recurrence, supporting the use of combined CAR-T therapies, perhaps directed at both CD19 and CD22.
Combining daratumumab with CD47 blockade prolongs survival in preclinical models of pediatric T-ALL
Müller et al explore the potential of dual antibody targeting of CD47 and CD38 in a preclinical models of T-ALL; although CD47 does not avoid the risk of aplasia, it shows efficacy in combination with daratumumab in treating relapsed T-ALL and eradicating MRD.
Impact of CD19 CAR T-cell product type on outcomes in relapsed or refractory aggressive B-NHL
CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cells are novel therapies showing great promise for patients with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL). Single-arm studies showed significant variations in outcomes across distinct CD19 CAR T-cell products. To estimate the independent impact of the CAR T-cell product type on outcomes, we retrospectively analyzed data from 129 patients with R/R aggressive B-NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by either a commercially available CD19 CAR T-cell therapy (axicabtagene ciloleucel [axicel] or tisagenlecleucel [tisacel]), or the investigational product JCAR014 on a phase 1/2 clinical trial (NCT01865617).
