CD19/CD22 targeting with cotransduced CAR T cells to prevent antigen-negative relapse after CAR T-cell therapy for B-cell ALL.

ABSTRACT: CD19-negative relapse is a leading cause of treatment failure after chimeric antigen receptor (CAR) T-cell therapy for acute lymphoblastic leukemia. We investigated a CAR T-cell product targeting CD19 and CD22 generated by lentiviral cotransduction with vectors encoding our previously described fast-off rate CD19 CAR (AUTO1) combined with a novel CD22 CAR capable of effective signaling at low antigen density. Twelve patients with advanced B-cell acute lymphoblastic leukemia were treated (CARPALL [Immunotherapy with CD19/22 CAR Redirected T Cells for High Risk/Relapsed Paediatric CD19+ and/or CD22+ Acute Lymphoblastic Leukaemia] study, NCT02443831), a third of whom had failed prior licensed CAR therapy. Toxicity was similar to that of AUTO1 alone, with no cases of severe cytokine release syndrome. Of 12 patients, 10 (83%) achieved a measurable residual disease (MRD)-negative complete remission at 2 months after infusion. Of 10 responding patients, 5 had emergence of MRD (n = 2) or relapse (n = 3) with CD19- and CD22-expressing disease associated with loss of CAR T-cell persistence. With a median follow-up of 8.7 months, there were no cases of relapse due to antigen-negative escape. Overall survival was 75% (95% confidence interval [CI], 41%-91%) at 6 and 12 months. The 6- and 12-month event-free survival rates were 75% (95% CI, 41%-91%) and 60% (95% CI, 23%-84%), respectively. These data suggest dual targeting with cotransduction may prevent antigen-negative relapse after CAR T-cell therapy.

Prevalence of adsorbed A antigen onto donor-derived group O red cells in children following stem cell transplantation: A single-centre evaluation.

BACKGROUND AND OBJECTIVES: A group AB D-positive child presented 1 year after haematopoietic stem cell transplant (HSCT) from a group O D-negative donor as group A D-negative. Engraftment remained at 100% in white cell lineages. The reason for the unusual result was explored, and the scarcely reported phenomenon of adsorption of secreted antigen was considered. This study also investigated the prevalence of secreted antigen adsorbed onto donor-derived group O red blood cells (RBCs) in children after HSCT and defined a process for laboratory management. MATERIALS AND METHODS: Retrospective data analysis of HSCTs carried out over 19 months at Great Ormond Street Hospital was conducted to identify cases of adsorbed A antigen after HSCT. Investigation of RBC reactions with different clones of anti-A and in vitro experiments was performed to recreate adsorption. RESULTS: Nineteen A to O HSCTs were conducted over 19 months, of which six (31%) displayed weak A antigen on RBCs despite full myeloid engraftment. Negative reactions with anti-A were obtained when run on an alternative clone. Laboratory protocols for the future management of these cases have been developed. CONCLUSION: Passive adsorption of secreted antigen is responsible for these results and is more widespread than previously reported, as a third of A to O HSCTs at our centre demonstrated this phenomenon. A process has been implemented into the laboratory to manage this cohort, ensuring component groups compatible with both donor and recipient are given, and the shared care centres are aware of these requirements.

Cytomegalovirus reactivation posthematopoietic stem cell transplantation (HSCT) and type of graft: A step toward rationalizing CMV testing and positively impacting the economics of HSCT in developing countries.

We aimed to determine a correlation between cytomegalovirus reactivation post hematopoeitic stem cell transplantation (post-HSCT) with the type of graft source, defining children at risk. We analyzed data on children less than 18 years of age undergoing HSCT from 2002 to May 2016 (n = 464). Correlation between reactivation and graft source was analyzed statistically. Reactivation occurred in 3% of children with matched-related donor (MRD) transplants, 33.3% with unrelated peripheral blood stem cells, 17.4% with unrelated cords, and 36.5% (15/41) with mismatched or haploidentical grafts (P = <0.0001). MRD does not warrant weekly PCR, unlike unrelated or haploidentical donors, thus defining protocols for developing countries with limited resources.

T-cell replete cord transplants give superior outcomes in high-risk and relapsed/refractory pediatric myeloid malignancy.

Stem cell transplant (SCT) outcomes in high-risk and relapsed/refractory (R/R) pediatric acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have been historically poor. Cord blood (CB) allows T-cell replete CB transplant (TRCB), enabling enhanced graft-versus-leukemia. We consecutively collected data from 367 patients undergoing TRCB (112 patients) or other cell source (255 patients) SCT for pediatric AML/MDS in the United Kingdom and Ireland between January 2014 and December 2021. Data were collected about the patient's demographics, disease, and its treatment; including previous transplant, measurable residual disease (MRD) status at transplant, human leukocyte antigen-match, relapse, death, graft versus host disease (GvHD), and transplant-related mortality (TRM). Univariable and multivariable analyses were undertaken. There was a higher incidence of poor prognosis features in the TRCB cohort: 51.4% patients were MRD positive at transplant, 46.4% had refractory disease, and 21.4% had relapsed after a previous SCT, compared with 26.1%, 8.6%, and 5.1%, respectively, in the comparator group. Event free survival was 64.1% within the TRCB cohort, 50% in MRD-positive patients, and 79% in MRD-negative patients. To allow for the imbalance in baseline characteristics, a multivariable analysis was performed where the TRCB cohort had significantly improved event free survival, time to relapse, and reduced chronic GvHD, with some evidence of improved overall survival. The effect appeared similar regardless of the MRD status. CB transplant without serotherapy may be the optimal transplant option for children with myeloid malignancy.

Profile of HIV and multidrug-resistant tuberculosis in orphans living in orphanages in Mumbai, Maharashtra, India.

AIMS: The aim was to study the clinical profile of HIV-infected orphans living in orphanages in Mumbai, Maharashtra, India and determine the prevalence of multidrug-resistant (MDR) tuberculosis (TB) in them. MATERIALS AND METHODS: Seventy-four HIV-infected orphans from two orphanages (orphanage A taking antiretroviral therapy [ART] as per our prescription, whereas orphanage B taking ART from an ART center) were included in the study. Detailed history and examination was carried out in each patient. CDC class prior to ART, age at presentation, CD4 count/percent, opportunistic infections (OIs) prior to and after ART, co-infections with hepatitis B virus (HBV) and hepatitis C virus, growth, ART regimes, and treatment failure were noted in each patient. RESULTS: Of 18 HIV-infected children in orphanage A, boys constituted 11 (61.1%) and girls were 7 (38.9%), whereas orphanage B had all girls (n = 56). TB was the most common OI in orphanage A prior to the start of ART seen in 15 (83.3%), whereas it was seen in 18 (32.1%) in orphanage B. In contrast, TB was seen in eight (14.2%) orphans in orphanage B after the start of ART, of which two (3.5%) were MDR-TB and another two (3.5%) were suspected to have MDR-TB, whereas one (5.5%) in orphanage A had MDR-TB. Age of presentation was 4.7 ± 3.2 years for orphanage A and 12.9 ± 2.5 years for orphanage B. On ART, malnutrition was seen in one child in orphanage A as compared to nine in orphanage B. ART was started at 6.1 ± 3.1 years in orphanage A and 10.1 ± 2.8 years in orphanage B. Zidovudine, lamivudine (3TC), and nevirapine (NVP)/efavirenz (EFV) constituted the baseline ART regimen in 13 (72.1%) orphans in orphanage A, whereas stavudine (d4T) + 3TC + NVP constituted the baseline ART in 17 (30.3%) orphans in orphanage B. Three (5.3%) orphans had HBV co-infection in orphanage B. CONCLUSION: Children in orphanage A came to us at a younger age, in more advanced stage of disease, and were more malnourished. Orphanage A was started on ART earlier in life. The prevalence of TB was higher in orphanage A prior to ART. MDR-TB was seen in both orphanages, with prevalence ranging from 3.5% to 5.5%.