Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas.

Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

A hormonal therapy for menopausal women with MS: A phase Ib/IIa randomized controlled trial.

INTRODUCTION: Most women develop MS before menopause. Menopausal hot flashes can worsen MS symptoms, and could be relieved with hormone therapy. Our objective was to evaluate feasibility, tolerability and symptom response of Duavee® (bazedoxifene + conjugated estrogen) in a Phase Ib/IIa double-blind randomized controlled clinical trial. METHODS: We randomized 24 peri/postmenopausal women with MS and symptomatic hot flashes 1:1 to Duavee® versus placebo. Evaluations occurred at baseline and 2 months. RESULTS: Groups were balanced for age (mean 51.2 ± 3.6 years), EDSS [median 3 (IQR:2.5, 4.5)], and MS duration. 21/24 participants completed the study. FEASIBILITY: Enrollment was protracted (34 months), partially due to concerns about hormone therapy safety. TOLERABILITY: treatment group participants reported greater satisfaction and fewer missed doses; one participant (placebo) developed new MRI lesions; liver function testing remained normal for all patients. SYMPTOMS: Hot Flash Related Daily Interference scale at 2 months was lower in treatment vs. placebo group [median (IQR) of 4 (0.5, 14) vs. 9 (0, 33)]. Between-group differences were not statistically significant. CONCLUSION: Despite perceived benefits in MS, estrogens have perceived risks that represent a hurdle to enrollment. With appropriate education and screening of participants, the favorable study retention (87%) and treatment satisfaction observed in the current study support the feasibility of a longer, powered trial to evaluate whether a proven treatment for menopausal symptoms, Duavee®, could also improve MS-related function in menopausal women with MS.

Experiences of sexual and gender minority people living with multiple sclerosis in Northern California: An exploratory study.

BACKGROUND: Sexual and gender minority (SGM) individuals may face unique challenges in accessing quality medical care due to structural disparities, social discrimination, and lack of culturally competent healthcare. Multiple sclerosis (MS) requires complex care. Little research has been carried out at the intersection between SGM identity and MS care. OBJECTIVE: To identify unmet clinical and social needs in our clinical population of SGM patients with MS. METHODS: Patients with MS who self-identified as SGM were recruited through the UCSF MS Center and a National MS Society web post to complete a 45-minute web-based (Qualtrics) survey. The mixed qualitative and quantitative survey covered experiences with different domains of MS care, drug/alcohol use, relationship status, social support, and participation in MS and SGM communities. RESULTS: Among the 26 survey respondents, mean age was 50.2 (SD 10.6) years; gender identity was women (46%) men (38%) and genderqueer, transgender, or other (15%); sexual orientation was gay/lesbian/bisexual (35%), pansexual/queer (27%), questioning (23%), or other identity (15%). Over two thirds (69%) of respondents were partnered. Overall satisfaction with MS care was high: 79.2% participants scored ≥4/5 (somewhat or extremely satisfied); participants dissatisfied with their care cited feeling dismissed. While 87.5% felt that their SGM identities did not affect their MS care, still 30% did report feeling uncomfortable discussing their SGM identities with their clinician. Participants rated low impact of having MS on participation in SGM communities (mean 2.4/5 on Likert scale); those participants reporting higher impact cited fatigue, immobility and stigmatization of disease as primary factors. Similarly, SGM status had low effect on participation in the MS community (mean 1.4/5); higher impact was related to apprehension around identity disclosure to new groups. Identified resources that might improve MS care included more representation, inclusivity and openness from clinicians, and SGM-focused MS support groups. DISCUSSION: In this exploratory survey of the needs of SGM people living with MS in Northern California, most participants reported that they were unlikely to participate in activities in the SGM community due to MS status or symptoms, however most felt that their SGM status did not affect their MS care. Given the center's location in a hub for SGM community and activism, surveying individuals in other settings would provide greater insights into the role of community, clinical support and the experience of SGM people living with MS.

Unmet Needs in the Evaluation, Treatment, and Recovery for 167 Children Affected by Acute Flaccid Myelitis Reported by Parents Through Social Media.

BACKGROUND: We aimed to characterize the outcomes of 167 children affected by acute flaccid myelitis by leveraging the power of social media. METHODS: Members of a closed social media (Facebook) group were invited to participate in an anonymous online survey. Descriptive statistics were applied to quantitative responses, and free-text responses were grouped into themes using a grounded theory approach. RESULTS: Caregivers provided information about 167 affected children; 77% were at least 6 months since onset. Clinical features matched those of larger published case series (e.g., walking impairment in 76.7%, intravenous immunoglobulin treatment in 80.8%; 28.2% tested positive for Enterovirus D68; 17% children had asthma before acute flaccid myelitis onset). Mean duration of initial hospitalization was 49.1 (S.D., 74.0) days, and of initial inpatient rehabilitation was 42.3 (S.D., 67.6) days. Among challenges, parents frequently reported delays in diagnosis, including lack of neurological examination at initial medical evaluation for weakness. Other challenges included familial and professional impact of protracted hospitalizations, uncertainty about cause or prognosis of acute flaccid myelitis, and the dynamic nature of care needs in growing children. The social media group played a critical role not only for social support but also for dissemination of rehabilitation approaches and of networks of expert clinicians. CONCLUSIONS: Children with acute flaccid myelitis have persistent and dynamic deficits, but many continue to show ongoing functional improvements beyond the initial expected window of recovery. In an emerging disease paralyzing young children, social media can strengthen knowledge networks and focus on rehabilitation.