Remission durability following single-antigen targeted chimeric antigen receptor (CAR) T-cells is limited by antigen modulation, which may be overcome with combinatorial targeting. Building upon our experiences targeting CD19 and CD22 in B-cell acute lymphoblastic leukemia (B-ALL), we report on the experiences and limitations of a novel MSCV-CD19/CD22-4-1BB bivalent CAR T-cell (CD19.22.BBz). This phase I dose-escalation trial enrolled children and young adults (CAYA) with B-cell malignancies. Primary objectives included toxicity and dose-finding. Secondary objectives included response rates and relapse-free survival (RFS). Biologic correlatives, including CAR T-cell expansion and cytokine profiling, and laboratory investigations, were also analyzed. Twenty patients, ages 5.4-34.6 years, with B-ALL received CD19.22.BBz. The complete response (CR) rate was 60% (12/20) in the full cohort and 71.4% (10/14) in CAR-naïve patients. Ten (50%) developed cytokine release syndrome (CRS), with 3 (15%) having grade 3 CRS and only 1 experiencing any neurotoxicity (grade 3). The 6- and 12-month RFS in those achieving CR was 80.8% (95% CI: 42.4-94.9%) and 57.7% (95% CI: 22.1-81.9%), respectively. Limited CAR T-cell expansion and persistence of MSCV-CD19.22.BBz compared to EF1a-CD22.BBz prompted laboratory investigations comparing EF1a versus MSCV promoters, which did not reveal major differences. Limited CD22 targeting with CD19.22.BBz, as evaluated by ex vivo cytokine secretion and leukemia eradication in humanized mice, led to development of a novel bicistronic CD19.28z/CD22.BBz construct with enhanced cytokine production against CD22. With demonstrated safety and efficacy of CD19.22.BBz in a heavily pre-treated CAYA B-ALL cohort, further optimization of combinatorial antigen targeting serves to overcome identified limitations. (Clinicaltrials.gov NCT03448393)
This case series describes 4 children with vertically acquired human immunodeficiency virus (HIV) infection who exhibited immunologic, virologic, and clinical stability while on a protease inhibitor-containing highly active antiretroviral therapy (HAART) regimen, yet demonstrated significant cognitive decline as measured by standardized intelligence tests. A retrospective review of 107 patient records of children with HIV infection on HAART treatment protocols was conducted. Four patients were identified who responded to protease inhibitor-containing HAART therapy with sustained viral load suppression, and stable immunologic and medical parameters, yet demonstrated significant cognitive decline. Such discordance between biological and clinical markers previously has been reported in adults with HIV disease but not in children. This observed decline in neurocognitive functioning despite stable medical parameters suggests that HAART regimens that are effective for systemic disease may not be as effective for the central nervous system (CNS), perhaps because the antiretrovirals do not penetrate adequately into the CNS. Of note, 3 of these 4 patients did not have zidovudine (ZDV) included in their HAART regimen. The only patient who was treated with ZDV containing regimen received 90 mg/m(2) every 6 hours, which is at the lower end of the recommended ZDV pediatric full-dose range (90 mg/m(2) to 120 mg/m(2)). Two of the 4 patients began ZDV at 120 mg/m(2) every 6 hours following the decline in their cognitive test scores and subsequently showed improved or stable functioning as evidenced by the results of follow-up psychometric testing. Long-term prospective studies using both systemic and CNS measures are necessary to further investigate the effects of HAART in children with HIV disease. Longitudinal cognitive assessments of children receiving HAART appear indicated to identify cognitive decline and to provide appropriate therapeutic intervention when manifestations of HIV-related CNS disease progression occur.
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