Stealth transgenes enable CAR-T cells to evade host immune responses.

BACKGROUND: Adoptive cell therapy, such as chimeric antigen receptor (CAR)-T cell therapy, has improved patient outcomes for hematological malignancies. Currently, four of the six FDA-approved CAR-T cell products use the FMC63-based αCD19 single-chain variable fragment, derived from a murine monoclonal antibody, as the extracellular binding domain. Clinical studies demonstrate that patients develop humoral and cellular immune responses to the non-self CAR components of autologous CAR-T cells or donor-specific antigens of allogeneic CAR-T cells, which is thought to potentially limit CAR-T cell persistence and the success of repeated dosing. METHODS: In this study, we implemented a one-shot approach to prevent rejection of engineered T cells by simultaneously reducing antigen presentation and the surface expression of both Classes of the major histocompatibility complex (MHC) via expression of the viral inhibitors of transporter associated with antigen processing (TAPi) in combination with a transgene coding for shRNA targeting class II MHC transactivator (CIITA). The optimal combination was screened in vitro by flow cytometric analysis and mixed lymphocyte reaction assays and was validated in vivo in mouse models of leukemia and lymphoma. Functionality was assessed in an autologous setting using patient samples and in an allogeneic setting using an allogeneic mouse model. RESULTS: The combination of the Epstein-Barr virus TAPi and an shRNA targeting CIITA was efficient and effective at reducing cell surface MHC classes I and II in αCD19 'stealth' CAR-T cells while retaining in vitro and in vivo antitumor functionality. Mixed lymphocyte reaction assays and IFNγ ELISpot assays performed with T cells from patients previously treated with autologous αCD19 CAR-T cells confirm that CAR T cells expressing the stealth transgenes evade allogeneic and autologous anti-CAR responses, which was further validated in vivo. Importantly, we noted anti-CAR-T cell responses in patients who had received multiple CAR-T cell infusions, and this response was reduced on in vitro restimulation with autologous CARs containing the stealth transgenes. CONCLUSIONS: Together, these data suggest that the proposed stealth transgenes may reduce the immunogenicity of autologous and allogeneic cellular therapeutics. Moreover, patient data indicate that repeated doses of autologous FMC63-based αCD19 CAR-T cells significantly increased the anti-CAR T cell responses in these patients.

Phase 1 study of CAR-37 T cells in patients with relapsed or refractory CD37+ lymphoid malignancies.

We report on the first-in-human clinical trial using chimeric antigen receptor (CAR) T-cells targeting CD37, an antigen highly expressed in B- and T-cell malignancies (clinicaltrials.gov NCT04136275). Five patients with relapsed or refractory CD37+ lymphoid malignancies were enrolled and infused with autologous CAR-37 T-cells. CAR-37 T-cells expanded in the peripheral blood of all patients and, at peak, comprised >94% of the total lymphocytes in 4/5 patients. Tumor responses were observed in 4/5 patients, with 3 complete responses, 1 mixed response, and 1 patient whose disease progressed rapidly and with relative loss of CD37 expression. Three patients experienced prolonged and severe pancytopenia, and in two of these patients, efforts to ablate CAR-37 T-cells (which were engineered to co-express truncated EGFR) with cetuximab, were unsuccessful. Hematopoiesis was restored in these two patients following allogeneic hematopoietic stem cell transplantation. No other severe, non-hematopoietic toxicities occurred. We investigated the mechanisms of profound pancytopenia and did not observe activation of CAR-37 T-cells in response to hematopoietic stem cells in vitro or hematotoxicity in humanized models. Patients with pancytopenia had sustained high levels of IL-18, with low levels of IL-18 binding protein in their peripheral blood. IL-18 levels were significantly higher in CAR-37-treated patients relative to both cytopenic and non-cytopenic cohorts of CAR-19-treated cohorts of patients. In conclusion, CAR-37 T-cells exhibited anti-tumor activity, with significant CAR expansion and cytokine production. CAR-37 T-cells may be an effective therapy in hematologic malignancies as a bridge to hematopoietic stem cell transplant.

Understanding the financial cost of cancer clinical trial participation.

BACKGROUND: Though financial hardship is a well-documented adverse effect of standard-of-care cancer treatment, little is known about out-of-pocket costs and their impact on patients participating in cancer clinical trials. This study explored the financial effects of cancer clinical trial participation. METHODS: This cross-sectional analysis used survey data collected in December 2022 and May 2023 from individuals with cancer previously served by Patient Advocate Foundation, a nonprofit organization providing social needs navigation and financial assistance to US adults with a chronic illness. Surveys included questions on cancer clinical trial participation, trial-related financial hardship, and sociodemographic data. Descriptive and bivariate analyses were conducted using Cramer's V to estimate the in-sample magnitude of association. Associations between trial-related financial hardship and sociodemographics were estimated using adjusted relative risks (aRR) and corresponding 95% confidence intervals (CI) from modified Poisson regression models with robust standard errors. RESULTS: Of 650 survey respondents, 18% (N = 118) reported ever participating in a cancer clinical trial. Of those, 47% (n = 55) reported financial hardship as a result of their trial participation. Respondents reporting trial-related financial hardship were more often unemployed or disabled (58% vs. 43%; V = 0.15), Medicare enrolled (53% vs. 40%; V = 0.15), and traveled >1 h to their cancer provider (45% vs. 17%; V = 0.33) compared to respondents reporting no hardship. Respondents who experienced trial-related financial hardship most often reported expenses from travel (reported by 71% of respondents), medical bills (58%), dining out (40%), or housing needs (40%). Modeling results indicated that respondents traveling >1 h vs. ≤30 min to their cancer provider had a 2.2× higher risk of financial hardship, even after adjusting for respondent race, income, employment, and insurance status (aRR = 2.2, 95% CI 1.3-3.8). Most respondents (53%) reported needing $200-$1000 per month to compensate for trial-related expenses. Over half (51%) of respondents reported less willingness to participate in future clinical trials due to incurred financial hardship. Notably, of patients who did not participate in a cancer clinical trial (n = 532), 13% declined participation due to cost. CONCLUSION: Cancer clinical trial-related financial hardship, most often stemming from travel expenses, affected almost half of trial-enrolled patients. Interventions are needed to reduce adverse financial participation effects and potentially improve cancer clinical trial participation.

Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma.

In this first-in-human, investigator-initiated, open-label study, three participants with recurrent glioblastoma were treated with CARv3-TEAM-E T cells, which are chimeric antigen receptor (CAR) T cells engineered to target the epidermal growth factor receptor (EGFR) variant III tumor-specific antigen, as well as the wild-type EGFR protein, through secretion of a T-cell-engaging antibody molecule (TEAM). Treatment with CARv3-TEAM-E T cells did not result in adverse events greater than grade 3 or dose-limiting toxic effects. Radiographic tumor regression was dramatic and rapid, occurring within days after receipt of a single intraventricular infusion, but the responses were transient in two of the three participants. (Funded by Gateway for Cancer Research and others; INCIPIENT ClinicalTrials.gov number, NCT05660369.).

A proactive financial navigation intervention in patients with newly diagnosed gastric and gastroesophageal junction adenocarcinoma.

PURPOSE: Many cancer patients and caregivers experience financial hardship, leading to poor outcomes. Gastric and gastroesophageal junction (GEJ) cancer patients are particularly at risk for financial hardship given the intensity of treatment. This pilot randomized study among gastric/GEJ cancer patients and caregivers tested a proactive financial navigation (FN) intervention to obtain a signal of efficacy to inform a larger, more rigorous randomized study. METHODS: We tested a 3-month proactive FN intervention among gastric/GEJ cancer patients and caregivers compared to usual care. Caregiver participation was optional. The primary endpoint was incidence of financial hardship, defined as follows: accrual of debt, income decline of ≥ 20%, or taking loans to pay for treatment. Data from participant surveys and documentation by partner organizations delivering the FN intervention was analyzed and outcomes were compared between study arms. RESULTS: Nineteen patients and 12 caregivers consented. Primary FN resources provided included insurance navigation, budget planning, and help with out-of-pocket medical expenses. Usual care patients were more likely to experience financial hardship (50% vs 40%) and declines in quality of life (37.5% vs 0%) compared to intervention patients. Caregivers in both arms reported increased financial stress and poorer quality of life over the study period. CONCLUSIONS: Proactive financial navigation has potentially positive impacts on financial hardship and quality of life for cancer patients and more large-scale randomized interventions should be conducted to rigorously explore the impact of similar interventions. Interventions that have the potential to lessen caregiver financial stress and burden need further exploration. TRIAL REGISTRATION: TRN: NCT03986502, June 14, 2019.

Optimization of a flow cytometry test for routine monitoring of B cell maturation antigen targeted CAR in peripheral blood.

Chimeric antigen receptor (CAR) modified T cell therapies targeting BCMA have displayed impressive activity in the treatment of multiple myeloma. There are currently two FDA licensed products, ciltacabtagene autoleucel and idecabtagene vicleucel, for treating relapsed and refractory disease. Although correlative analyses performed by product manufacturers have been reported in clinical trials, there are limited options for reliable BCMA CAR T detection assays for physicians and researchers looking to explore it as a biomarker for clinical outcome. Given the known association of CAR T cell expansion kinetics with toxicity and response, being able to quantify BCMA CAR T cells routinely and accurately in the blood of patients can serve as a valuable asset. Here, we optimized an accurate and sensitive flow cytometry test using a PE-conjugated soluble BCMA protein, with a lower limit of quantitation of 0.19% of CD3+ T cells, suitable for use as a routine assay for monitoring the frequency of BCMA CAR T cells in the blood of patients receiving either ciltacabtagene autoleucel or idecabtagene vicleucel.

Anti-TACI single and dual-targeting CAR T cells overcome BCMA antigen loss in multiple myeloma.

Chimeric Antigen Receptor (CAR) T cells directed to B cell maturation antigen (BCMA) mediate profound responses in patients with multiple myeloma, but most patients do not achieve long-term complete remissions. In addition, recent evidence suggests that high-affinity binding to BCMA can result in on-target, off-tumor activity in the basal ganglia and can lead to fatal Parkinsonian-like disease. Here we develop CAR T cells against multiple myeloma using a binder to targeting transmembrane activator and CAML interactor (TACI) in mono and dual-specific formats with anti-BCMA. These CARs have robust, antigen-specific activity in vitro and in vivo. We also show that TACI RNA expression is limited in the basal ganglia, which may circumvent some of the toxicities recently reported with BCMA CARs. Thus, single-targeting TACI CARs may have a safer toxicity profile, whereas dual-specific BCMA-TACI CAR T cells have potential to avoid the antigen escape that can occur with single-antigen targeting.

Fractionated vs single-dose gemtuzumab ozogamicin with determinants of benefit in older patients with AML: the UK NCRI AML18 trial.

Addition of gemtuzumab ozogamicin (GO) to induction chemotherapy improves outcomes in older patients with acute myeloid leukemia (AML), but it is uncertain whether a fractionated schedule provides additional benefit to a single dose. We randomized 852 older adults (median age, 68-years) with AML/high-risk myelodysplasia to GO on day 1 (GO1) or on days 1 and 4 (GO2) of course 1 induction. The median follow-up period was 50.2 months. Although complete remission (CR) rates after course 1 did not significantly differ between arms (GO2, 63%; GO1, 57%; odds ratio [OR], 0.78; P = .08), there were significantly more patients who achieved CR with a measurable residual disease (MRD)<0.1% (50% vs 41%; OR, 0.72; P = .027). This differential MRD reduction with GO2 varied across molecular subtypes, being greatest for IDH mutations. The 5-year overall survival (OS) was 29% for patients in the GO2 arm and 24% for those in the GO1 arm (hazard ratio [HR], 0.89; P = .14). In a sensitivity analysis excluding patients found to have adverse cytogenetics or TP53 mutations, the 5-year OS was 33% for GO2 and 26% for GO1 (HR, 0.83; P = .045). In total, 228 (27%) patients received an allogeneic transplantation in first remission. Posttransplant OS was superior in the GO2 arm (HR, 0.67; P = .033); furthermore, the survival advantage from GO2 in the sensitivity analysis was lost when data of patients were censored at transplantation. In conclusion, GO2 was associated with a greater reduction in MRD and improved survival in older adults with nonadverse risk genetics. This benefit from GO2 was dependent on allogeneic transplantation to translate the better leukemia clearance into improved survival. This trial was registered at www.isrctn.com as #ISRCTN 31682779.

A nationwide cross-sectional study on the association of patient-level factors with financial anxiety in the context of chronic medical conditions.

Patient-level characteristics associated with the prevalence and severity of financial anxiety have yet to be described. We conducted a cross-sectional analysis of survey data assessing financial anxiety in patients with chronic medical conditions in December 2020. 1771 patients (42.6% response rate) participated in the survey. Younger age (19-35 age compared to ≥ 75 age) (ß, 5.86; 95% CI 2.10-9.63), male sex (ß, - 1.9; 95% CI - 3.1 to - 0.73), Hispanic/Latino race/ethnicity (compared with White patients) (ß, 2.55; 95% CI 0.39-4.71), household size ≥ 4 (compare with single household) (ß, 4.54; 95% CI 2.44-6.64), household income of ≥ $96,000-$119,999 (compared with ≤ $23,999) (ß, - 3.2; 95% CI - 6.3 to 0.04), single marital status (compared with married) (ß, 2.18; 95% CI 0.65-3.71), unemployment (ß, 2.07; 95% CI 0.39-3.74), high-school education (compared with advanced degrees) (ß, 3.10; 95% CI 1.32-4.89), lack of insurance coverage (compared with private insurance) (ß, 6.05; 95% CI 2.66-9.45), more comorbidities (≥ 3 comorbidities compared to none) (ß, 2.95; 95% CI 1.00-4.90) were all independently associated with financial anxiety. Patients who are young, female, unmarried, and representing vulnerable sub-populations are at elevated risk for financial anxiety.

Facing financial barriers to healthcare: patient-informed adaptation of a conceptual framework for adults with a history of cancer.

Background: Cancer-related financial hardship is associated with negative clinical outcomes, which may be partially explained by cost-related delayed or forgone care in response to financial barriers. We sought to understand patient experiences facing financial barriers to medical care following a cancer diagnosis. Methods: We conducted virtual, semi-structured interviews in Fall 2022 with 20 adults with a history of cancer who had experienced cancer-related financial hardship in the prior year. We used template analysis within a pragmatic paradigm, combining constructivist and critical realist theoretical perspectives, to analyze interview transcripts and adapt an existing conceptual framework of financial barriers to care. Results: The majority of interviewees identified as women (70%), non-Hispanic white (60%), and reported an annual household income of <$48,000 (60%). As interviewees sought to overcome financial barriers, they described substantial frustration at the limitations and complexities of United States health and social care systems, resulting in a reliance on a fragmented, uncertain resource landscape. The administrative burden resulting from bureaucratic systems and the advocacy responsibilities required to navigate them ultimately fell on interviewees and their caregivers. Thus, participants described their ability to overcome financial barriers as being influenced by individual and interpersonal factors, such as social support, comfort asking for help, time, prior experience navigating resources, and physical and mental health. However, participants noted health system organizational factors, such as whether all new patients proactively met with a social worker or financial navigator, as having the potential to lessen the administrative and financial burden experienced. Conclusion: We present an adapted conceptual framework outlining multi-level factors influencing patient experiences coping with financial barriers to medical care. In addition to influencing whether a patient ultimately delays or forgoes care due to cost, financial barriers also have the potential to independently affect patient mental, physical, and financial health.

Rationale and design of a pilot randomized controlled trial to increase moderate-to-vigorous physical activity in preadolescent Latina girls and their mothers.

Background: Hispanic/Latina girls have a low prevalence of moderate-intensity physical activity (PA) compared to their male counterparts and non-Hispanic White girls. Mothers influence their children's activity levels by creating and supporting PA opportunities, modeling PA, and reinforcing children's efforts to be physically active. The Conmigo trial will evaluate a mother-daughter intervention to promote PA and examine potential mechanisms of change including mothers' PA, parenting regarding PA, and mother-daughter communication. Method: This randomized controlled trial examines the feasibility, acceptability, and impact of a 12-week intervention promoting PA in preadolescent Latina girls in San Diego County, CA. Participants (n = 90 dyads) are randomized to the Conmigo PA intervention or to a control group that receive an abbreviated version of the intervention. The intervention was informed by Social Cognitive Theory and Family Systems Theory and emphasize family-level factors to promote PA using an actor-partner model. Mothers and daughters attend weekly 90-min sessions in English or in Spanish via Zoom video conferencing, supported by facilitator follow-ups and WhatsApp supportive chat group for mothers. Objective (accelerometer) and self-report measures at baseline, 3 months, and 6 months capture the frequency and intensity of PA and correlates and predictors of PA. We also examine the impact of the intervention on the bidirectional influence of mother-daughter PA. Implications: The findings from the Conmigo trial will form the basis of a randomized controlled community trial and will move the field forward in identifying targets of change in preventing chronic disease risk in Hispanic/Latino communities.

Food as a Driver of a Cholera Epidemic in Jijiga, Ethiopia-June 2017.

We conducted a case-control study to identify risk and protective factors during a cholera outbreak in Jijiga, Ethiopia, in June 2017. A case-patient was defined as anyone > 5 years old with at least three loose stools in 24 hours who was admitted to a cholera treatment center in Jijiga on or after June 16, 2017. Two controls were matched to each case by type of residency (rural or urban) and age group. We enrolled 55 case-patients and 102 controls from June 16 to June 23, 2017. Identified risk factors for cholera were male sex, eating cold food, and eating food outside the home. Eating hot food was protective, as was reported handwashing after defecation; no other reported water, sanitation, and hygiene factors were associated with cholera risk. Recommendations included continuing messaging about safe food handling practices at home, the dangers of consuming meals prepared away from home, and the importance of hand hygiene practices.

Barriers to COVID-19 vaccine uptake among resource-limited adults diagnosed with chronic illness.

Background: Despite the use of interventions (e.g., monetary incentives, educational campaigns, on-site workplace vaccination) to increase COVID-19 vaccination, differences in uptake persist by poverty level, insurance status, geography, race, and ethnicity, suggesting that these interventions may not be adequately addressing the barriers faced by these populations. Among a sample of resource-limited individuals with chronic illnesses, we (1) described the prevalence of different types of barriers to the COVID-19 vaccination and (2) identified associations between patients' sociodemographic characteristics and barriers to vaccination. Methods: We surveyed a national sample of patients with chronic illness and demonstrated healthcare affordability and/or access challenges about barriers to COVID-19 vaccination in July 2021. We categorized participant responses into cost, transportation, informational, and attitudinal barrier domains and assessed the prevalence of each domain, both overall and by self-reported vaccination status. Using logistic regression models, we examined unadjusted and adjusted associations between respondent characteristics (sociodemographic, geographic, and healthcare access) and self-reported barriers to vaccination. Results: Of 1,342 respondents in the analytic sample, 20% (264/1,342) reported informational barriers and 9% (126/1,342) reported attitudinal barriers to COVID-19 vaccination. Transportation and cost barriers were reported much less commonly, by only 1.1% (15/1,342) and 0.7% (10/1,342) of the sample, respectively. Controlling for all other characteristics, respondents with either a specialist as their usual source of care or no usual source of care had an 8.4 (95% CI: 1.7-15.1) and 18.1 (95% CI: 4.3-32.0) percentage point higher predicted probability, respectively, of reporting informational barriers to care. Compared to females, males had an 8.4% point (95% CI: 5.5-11.4) lower predicted probability of reporting attitudinal barriers. Only attitudinal barriers were associated with COVID-19 vaccine uptake. Conclusion: Among a sample of adults with chronic illnesses who had received financial assistance and case management services from a national non-profit, informational and attitudinal barriers were more commonly reported than logistical or structural access barriers (i.e., transportation and cost barriers). Interventions should target attitudinal barriers among patients with chronic illness, who may have particular concerns about the interaction of the vaccine with ongoing medical care. Additionally, interventions targeting informational barriers are particularly needed among individuals without a usual source of care.

Patient-reported discrimination among limited-resourced cancer survivors: a brief report.

PURPOSE: Healthcare discrimination has been associated with health disparities including lower cancer screenings, higher medical mistrust, and strained patient-provider relationships. Our study sought to understand patient-reported discrimination among cancer survivors with limited resources living in the United States. DESIGN AND METHODS: We used cross-sectional survey data distributed by the Patient Advocate Foundation (PAF) in 12/2020 and 07/2021. Respondents reported source and reason of healthcare discrimination. Age, sex, race and ethnicity, annual household income, Rural-Urban Commuting Area (RUCA), Area Deprivation Index (ADI), employment status, cancer type, and number of comorbidities were independent variables of interest. The association between these variables and patient-reported healthcare discrimination was estimated using risk ratios (RRs) and 95% confidence intervals (CIs) from a multivariable modified Poisson regression model with robust standard errors. FINDINGS: A total of 587 cancer survivors were included in our analysis. Most respondents were female (72%) and aged ≥56 (62%); while 33% were Black, Indigenous, or Person of Color. Overall, 23% reported receipt of discrimination, with the majority reporting doctor, nurse, or healthcare provider as the source (58%). Most common reasons for discrimination included disease status (42%), income/ability to pay (36%), and race and ethnicity (17%). In the adjusted model, retired survivors were 62% less likely to report discrimination compared to those employed (RR 0.38; 95% CI 0.23-0.64). Additionally, survivors with ≥3 comorbidities were 86% more likely to report discrimination compared to those survivors with no non-cancer comorbidities (RR 1.86; 95% CI 1.26-2.72). IMPLICATIONS: Cancer survivors with limited resources reported substantial discrimination most often from a healthcare provider and most commonly for disease status and income. Discrimination should be mitigated to provide equitable and high-quality cancer care.

Rapid virtual training and field deployment for COVID-19 surveillance officers: experiences from Ethiopia.

Rapid scale-up of surveillance activities is the key to successful coronavirus disease 2019 (COVID-19) pandemic prevention and mitigation. Ethiopia did not have a sufficient number of active surveillance officers for the public health COVID-19 response. Training of surveillance officers was needed urgently to fill the gap in the workforce needed. Subject-matter experts from the United States and Ethiopia developed applicable training modules including background on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), contact investigation, and communications. The training modules were delivered live in real-time via web-based virtual presentation. Seventy-seven health surveillance officers were hired, trained, and deployed in two weeks to assist with surveillance activities in Ethiopia. Electronic capacity building is needed in order to improve Web-based training in resource-limited settings where internet access is limited or unreliable. Web-based synchronously delivered course was an effective platform for COVID-19 surveillance training. However, strengthening public and private information technology capacity, literacy, and internet availability will improve Web-based education platforms in resource-limited countries.

Extending and Strengthening Routine DHIS2 Surveillance Systems for COVID-19 Responses in Sierra Leone, Sri Lanka, and Uganda.

The COVID-19 pandemic challenged countries to protect their populations from this emerging disease. One aspect of that challenge was to rapidly modify national surveillance systems or create new systems that would effectively detect new cases of COVID-19. Fifty-five countries leveraged past investments in District Health Information Software version 2 (DHIS2) to quickly adapt their national public health surveillance systems for COVID-19 case reporting and response activities. We provide background on DHIS2 and describe case studies from Sierra Leone, Sri Lanka, and Uganda to illustrate how the DHIS2 platform, its community of practice, long-term capacity building, and local autonomy enabled countries to establish an effective COVID-19 response. With these case studies, we provide valuable insights and recommendations for strategies that can be used for national electronic disease surveillance platforms to detect new and emerging pathogens and respond to public health emergencies.

Vaccine Hesitancy versus Vaccine Behavior in Patients with Chronic Illness.

While vaccine hesitancy has been described for the general population, vaccine hesitancy among the chronically ill has not been well explored. This study assesses COVID­19 vaccine hesitancy and uptake among individuals with chronic illness using nationwide survey data. We analyzed vaccine hesitancy prior to and after approval of the vaccines using multinomial logistic regression and binomial logistic regression, respectively. In the first survey, 39% reported they were unlikely or unsure about receiving the vaccine. In adjusted analyses, female sex, Black race, anti­vaccination attitudes, media mistrust, and not following the media were associated with vaccine hesitancy. Despite this hesitance, in the follow­up survey, 89% reported vaccine receipt, with those more fearful of COVID­19, with more trust in the media, and closely following the development of the vaccine were most likely to move from hesitance to acceptance. Vaccine hesitancy is a mutable characteristic, underscoring the need for high-quality public health messaging.

Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma.

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. Approximately half of patients with refractory large B cell lymphomas achieve durable responses from CD19-targeting CAR-T treatment; however, failure mechanisms are identified in only a fraction of cases. To gain new insights into the basis of clinical response, we performed single-cell transcriptome sequencing of 105 pretreatment and post-treatment peripheral blood mononuclear cell samples, and infusion products collected from 32 individuals with large B cell lymphoma treated with either of two CD19 CAR-T products: axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Expansion of proliferative memory-like CD8 clones was a hallmark of tisa-cel response, whereas axi-cel responders displayed more heterogeneous populations. Elevations in CAR-T regulatory cells among nonresponders to axi-cel were detected, and these populations were capable of suppressing conventional CAR-T cell expansion and driving late relapses in an in vivo model. Our analyses reveal the temporal dynamics of effective responses to CAR-T therapy, the distinct molecular phenotypes of CAR-T cells with differing designs, and the capacity for even small increases in CAR-T regulatory cells to drive relapse.

U.S. CDC support to international SARS-CoV-2 seroprevalence surveys, May 2020-February 2022.

SARS-CoV-2 seroprevalence surveys provide critical information to assess the burden of COVID-19, describe population immunity, and guide public health strategies. Early in the pandemic, most of these surveys were conducted within high-income countries, leaving significant knowledge gaps in low-and middle-income (LMI) countries. To address this gap, the U.S. Centers for Disease Control and Prevention (CDC) is supporting serosurveys internationally. We conducted a descriptive analysis of international serosurveys supported by CDC during May 12, 2020-February 28, 2022, using an internal tracker including data on the type of assistance provided, study design, population surveyed, laboratory testing performed, and status of implementation. Since the beginning of the pandemic, CDC has supported 72 serosurveys (77 serosurvey rounds) in 35 LMI countries by providing technical assistance (TA) on epidemiologic, statistical, and laboratory methods, financial assistance (FA), or both. Among these serosurvey rounds, the majority (61%) received both TA and FA from CDC, 30% received TA only, 3% received only FA, and 5% were part of informal reviews. Fifty-four percent of these serosurveys target the general population, 13% sample pregnant women, 7% sample healthcare workers, 7% sample other special populations (internally displaced persons, patients, students, and people living with HIV), and 18% assess multiple or other populations. These studies are in different stages of implementation, ranging from protocol development to dissemination of results. They are conducted under the leadership of local governments, who have ownership over the data, in collaboration with international partners. Thirty-four surveys rounds have completed data collection. CDC TA and FA of SARS-CoV-2 seroprevalence surveys will enhance the knowledge of the COVID-19 pandemic in almost three dozen LMI countries. Support for these surveys should account for current limitations with interpreting results, focusing efforts on prospective cohorts, identifying, and forecasting disease patterns over time, and helping understand antibody kinetics and correlates of protection.