Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery.

To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRß chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A∗02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer.

GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas.

Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system1. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 106 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly3. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.

A Phase 1 Clinical Trial of NKTR-255 with CD19-22 CAR-T Cell Therapy for Refractory B-cell Acute Lymphoblastic Leukemia.

While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).

A randomized, double-blind, phase III study assessing clinical similarity of SB17 (proposed ustekinumab biosimilar) to reference ustekinumab in subjects with moderate-to-severe plaque psoriasis.

BACKGROUND: Ustekinumab (UST) is a safe and effective treatment for moderate-to-severe psoriasis. OBJECTIVES: To compare efficacy, safety, pharmacokinetics (PK), and immunogenicity of the proposed UST biosimilar SB17 with reference UST in subjects with moderate-to-severe plaque psoriasis. METHODS: In this randomized double-blind study, subjects were randomized to receive 45 mg of SB17 or UST subcutaneously at week 0, 4, and every 12 weeks. The primary endpoint was the percent change from baseline in Psoriasis Area and Severity Index at week 12 with an equivalence margin of [-15%, 15%]. Other secondary efficacy, safety, PK, and immunogenicity endpoints were measured through week 28. RESULTS: Two hundred forty-nine subjects were randomized to SB17, 254 to UST. Adjusted difference of Psoriasis Area and Severity Index change from baseline at week 12 of -0.6% (95% confidence interval; -3.780, 2.579) was within the equivalence margin. Physician's Global Assessment and Dermatology Life Quality Index were also comparable. Overall treatment-emergent adverse events were comparable (SB17: 48.2%, UST: 48.8%). The overall incidence of antidrug antibodies up to Week 28 was 13.3% with SB17 and 39.4% with UST. LIMITATIONS: Data were only through week 28. CONCLUSION: SB17 was clinically biosimilar to UST up to week 28.

Vaccination recommendations for adults receiving biologics and oral therapies for psoriasis and psoriatic arthritis: Delphi consensus from the medical board of the National Psoriasis Foundation.

BACKGROUND: For psoriatic patients who need to receive nonlive or live vaccines, evidence-based recommendations are needed regarding whether to pause or continue systemic therapies for psoriasis and/or psoriatic arthritis. OBJECTIVE: To evaluate literature regarding vaccine efficacy and safety and to generate consensus-based recommendations for adults receiving systemic therapies for psoriasis and/or psoriatic arthritis receiving nonlive or live vaccines. METHODS: Using a modified Delphi process, 22 consensus statements were developed by the National Psoriasis Foundation Medical Board and COVID-19 Task Force, and infectious disease experts. RESULTS: Key recommendations include continuing most oral and biologic therapies without modification for patients receiving nonlive vaccines; consider interruption of methotrexate for nonlive vaccines. For patients receiving live vaccines, discontinue most oral and biologic medications before and after administration of live vaccine. Specific recommendations include discontinuing most biologic therapies, except for abatacept, for 2-3 half-lives before live vaccine administration and deferring next dose 2-4 weeks after live vaccination. LIMITATIONS: Studies regarding infection rates after vaccination are lacking. CONCLUSION: Interruption of antipsoriatic oral and biologic therapies is generally not necessary for patients receiving nonlive vaccines. Temporary interruption of oral and biologic therapies before and after administration of live vaccines is recommended in most cases.

Choosing Systemic Agents for Psoriasis.

Treatment options for moderate-to-severe psoriasis depend on drug efficacy and safety, patient preferences, comorbidities, and cost-no drug dominates across all dimensions. Interleukin (IL)-17 inhibitors may be preferred for fast-acting treatment, while the 3-month schedule of risankizumab, ustekinumab, or tildrakizumab may be attractive for patients who prioritize fewer injections. Phototherapy is suitable for patients who wish to avoid systemic agents or when cost is a concern. For patients with poor adherence, infliximab or tildrakizumab may be well suited as they require in-office administration. Dermatologists can educate patients on available therapies to find a regimen best suited to their needs.

A Review of Topical Tapinarof for the Treatment of Plaque Psoriasis.

OBJECTIVE: This article reviews the efficacy and safety of 1% tapinarof cream for plaque psoriasis. DATA SOURCES: A literature search was conducted from August 2022 to February 2023. The terms tapinarof, VTAMA, benvitimod, GSK2894512, DMVT-505, and WBI-1001 were queried in PubMed. ClinicalTrials.gov was searched to identify ongoing or unpublished studies. STUDY SELECTION AND DATA EXTRACTION: All clinical trials written in English and relevant to pharmacology, efficacy, and safety were included. DATA SYNTHESIS: In two 12-week phase III clinical trials, disease severity assessed by a Physician's Global Assessment (PGA) score of clear or almost clear and a 2-point PGA improvement was 35.4% and 40.2% at week 12 in the 2 trials, respectively. In the 40-week, open-label extension trial, the efficacy and safety results were similar: 40.9% of patients achieved a PGA of 0 at least once during the trial, and 58.2% of patients with PGA ≥ 2 achieved PGA 0/1 at least once. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS: Tapinarof is a topical aryl hydrocarbon receptor agonist and a first-in-class, potentially promising treatment for plaque psoriasis recently approved by the U.S. Food and Drug Administration. CONCLUSION: Compared with placebo, tapinarof may be an effective and safe topical treatment for mild to severe plaque psoriasis. Head-to-head trials to compare the efficacy and adverse effect profile of tapinarof to other topical treatments are still needed, as are investigation in patients with recent or current use of phototherapy or biologic or nonbiologic systemics. Cost and adherence to treatment may be barriers for treatment efficacy.

A Review of Topical Sirolimus for the Treatment of Facial Angiofibromas in Tuberous Sclerosis Complex.

OBJECTIVE: This article assesses the efficacy, safety, pharmacology, and clinical applications of topical sirolimus 0.2% gel for the treatment of tuberous sclerosis complex (TSC)-associated facial angiofibromas. DATA SOURCES: A review of the literature was conducted using the Medline (PubMed) and EMBASE databases using the keywords topical sirolimus, rapamycin, Hyftor, and tuberous sclerosis. STUDY SELECTION AND DATA EXTRACTION: Articles written in English and relevant to the topic were included. DATA SYNTHESIS: In the phase 2 trial, the mean improvement factor, a composite measure of improved tumor size and redness, was achieved in all patient groups (P < 0.001) with significant responses among the adult and pediatric subgroups at week 12. There were no serious adverse events recorded. In the phase 3 trial, 60% of participants responded to treatment in the sirolimus group compared with 0% in the placebo group with different response rates between the adult and pediatric subgroups at week 12. Sirolimus gel had no serious adverse events, and dry skin was the most common adverse reaction. Patients who had completed the 12-week trials were then enrolled in a long-term trial; angiofibromas had response rates of 78.2% to 0.2% sirolimus gel. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS: Topical sirolimus 0.2% is a first-in-class, newly Food and Drug Administration (FDA)-approved, mammalian target of rapamycin (mTOR) inhibitor that is a promising and safe, noninvasive alternative to surgical procedures for TSC-associated angiofibromas. CONCLUSIONS: Topical sirolimus 0.2% gel is a moderately effective treatment for TSC-associated facial angiofibromas with an adequate safety profile.

Spesolimab: A Review of the First IL-36 Blocker Approved for Generalized Pustular Psoriasis.

OBJECTIVE: This article reviews clinical trial data that assesses the safety, efficacy, and clinical application of spesolimab, an interleukin-36 (IL-36) blocker, for the treatment of generalized pustular psoriasis (GPP). DATA SOURCES: A review of the literature was conducted using the search terms: "spesolimab," "BI 655130," and "spevigo" in MEDLINE (PubMed) and Clinicaltrials.gov from January 1, 1950 to October 31, 2023. STUDY SELECTION AND DATA EXTRACTION: Relevant articles in English relating to the pharmacodynamics, pharmacokinetics, efficacy, and safety of spesolimab were included. DATA SYNTHESIS: In one phase 2 clinical trial evaluating single dose IV spesolimab for GPP flares at day 8, 54% of patients receiving spesolimab had a GPP physician global assessment (GPPGA) pustulation subscore of 0, and 43% had a GPPGA total score of 0 compared with 6% and 11% for the placebo group, respectively. Another phase 2 clinical trial assessing subcutaneous spesolimab found 23% of patients in low-dose, 29% in medium-dose, and 10% of high-dose spesolimab had flares by week 48 compared with 52% of the placebo group. Hazard ratios for time to GPP flare compared with placebo were 0.16 (P = 0.0005), 0.35 (P = 0.0057), and 0.47 (P = 0.027) for the spesolimab groups, respectively. Infection rates were similar across treatment and placebo groups, and severe adverse events such as drug reactions with eosinophilia and systemic symptom (DRESS), cholelithiasis, and breast cancer occurred with spesolimab. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS: Spesolimab is a first-in-class IL-36 monoclonal antibody receptor antagonist approved for the treatment of acute GPP flares. It is a safe and effective therapeutic agent in preventing future GPP flares, with no current comparator trials with other GPP agents. CONCLUSION: Spesolimab is a safe and effective treatment for acute GPP flares in adults. Future clinical trials can establish safety and efficacy compared with other agents.

Qualitative investigation of disease course, characteristics and lived experience of generalized pustular psoriasis.

BACKGROUND: Generalized pustular psoriasis (GPP) is a relapsing-remitting chronic disease characterized by painful pustules with systemic symptoms that negatively impacts quality of life. The psychosocial and economic burden of this rare condition is not well characterized. OBJECTIVES: To qualitatively characterize the cumulative burden of generalized pustular psoriasis on patients' quality of life and psychosocial wellbeing. METHODS: A retrospective chart review of patients with generalized pustular psoriasis was performed to collect demographic information, followed by prospective semi-structured clinical interviews. Interview transcripts were analyzed using thematic analysis. RESULTS: Three major themes were revealed: (1) Burden of having a chronic disease with an unpredictable course, (2) an inability to fulfill societal roles results in a loss of identity, and (3) a physician-patient relationship grounded in trust and transparency can be invaluable in helping patients endure chronic disease. CONCLUSION: GPP has a negative impact on patients' quality of life and psychosocial wellbeing. Impairments in daily function and mental health primarily affects patients during flares and influences behavior during periods of quiescence. A strong patient-physician relationship may help mitigate the impact of GPP.

Dermatologists' Perspectives on Biosimilars.

BACKGROUND: Biosimilars are biologic agents the Food and Drug Administration (FDA) has deemed to have no clinical difference from their reference biologics. In dermatology,  biosimilars are approved for the treatment of psoriasis and hidradenitis suppurativa. Although dermatologists are high prescribers of biologics, they are more reluctant to prescribe biosimilars than other specialists. This survey-based study sought to characterize dermatologists’ current perspectives on biosimilars.  Methods: A 27-question survey was distributed via email to dermatologists between September and October of 2022.  Results: Twenty percent of respondents would not prescribe a biosimilar for an FDA-approved indication. When asked about the greatest barriers to biosimilar adoption, 61% had concerns about biosimilar safety and efficacy, 24% reported uncertainty about state laws for interchangeability and substitutions, and 20% had concerns about biosimilar safety without concerns about efficacy. Thirty-five percent of respondents felt moderately or extremely knowledgeable about biosimilar interchangeability.  Conclusion: Biosimilars are safe and effective for treating approved dermatological conditions and may lower patient costs compared to their reference products. Patients are not always offered biosimilar therapy as an option, which may be due to unfamiliarity among dermatologists.  This survey suggests a need for more research and educational initiatives, such as modules and workshops that focus on biosimilar safety, efficacy, and interchangeability guidelines. J Drugs Dermatol. 2024;23(4):doi:10.36849/JDD.7755.

Number of Affected Nails Is the Primary Determinant of Efinaconazole 10% Solution Usage for Onychomycosis.

Good adherence to treatment is necessary for the successful treatment of onychomycosis and requires that an appropriate amount of medication be prescribed. Most prescriptions for efinaconazole 10% solution, a topical azole antifungal, are for 4 mL per month but there are no data on patient factors or disease characteristics that impact how much medication is needed. Data from two phase 3 studies of efinaconazole 10% solution for the treatment of toenail onychomycosis were pooled and analyzed to determine monthly medication usage based on the number of affected toenails, percent involvement of the target toenail, body mass index (BMI), and sex. Participants with two or more affected nails required, on average, >4 mL of efinaconazole per month, with increasing amounts needed based on the number of nails with onychomycosis (mean: 4.39 mL for 2 nails; 6.36 mL for 6 nails). In contrast, usage was not greatly impacted by target toenail involvement, BMI, or sex. Together, these data indicate that the number of affected nails should be the major consideration when determining the monthly efinaconazole quantity to prescribe. J Drugs Dermatol. 2024;23(2):110-112.    doi:10.36849/JDD.7676.

Benefit of Topical Combination Therapy for Acne: Analyzing Effect Size Using Number Needed to Treat.

BACKGROUND: Topical acne trials often are confounded by high vehicle response rates and differing outcome measures, making it difficult to compare treatments. Number needed to treat (NNT) can be a simple, clinically meaningful way to indirectly compare treatment options without head-to-head data. NNT is the number of patients who need to be treated with an intervention to observe one additional patient successfully achieving a desired outcome versus vehicle/placebo. While treatment attributes such as adverse events may not be captured, lower NNT is a good indicator of a more effective treatment. METHODS: Following a search of combination topical treatments for acne vulgaris, all treatments that reported pivotal trial efficacy data consistent with the 2018 FDA definition of success were included in NNT analyses.  Results: Of 13 treatments, 7 reported 12-week treatment success rates in 11 phase 3 trials, with similar baseline demographics/disease severity. Treatment success ranged from 26.8% with tretinoin 0.1%/benzoyl peroxide (BPO) 3% cream to 50% with triple-combination clindamycin phosphate 1.2%/adapalene 0.15%/BPO 3.1% gel. NNTs for the triple-combination gel were 4 and 5 (from 2 pivotal trials). Adapalene 0.3%/BPO 2.5% gel had an NNT of 5. Tretinoin/BPO had the largest range between trials, with NNTs of 4 and 9. The other 4 treatments had NNTs ranging from 6 to 8. CONCLUSION: A comparison of combination topical acne treatment trial data, using the same treatment outcome and similar patient populations, resulted in triple-combination clindamycin phosphate/adapalene/BPO gel and adapalene/BPO gel having the most favorable NNTs.J Drugs Dermatol. 2024;23(2):42-49.  doi:10.36849/JDD.7927.

Adherence in Atopic Dermatitis.

Atopic dermatitis is a chronic dermatologic condition requiring extended treatment times with topical application of medications. While atopic dermatitis treatments can be highly effective when used as directed, oftentimes patients do not respond as expected, raising concern for nonadherence versus nonresponse. This chapter aims to describe what is currently known about adherence in atopic dermatitis and to discuss strategies to improve adherence in order to improve treatment outcomes. Whether intentional or unintentional, nonadherence to treatment can limit patient outcomes of this disease for a variety of reasons. These include frustration with medication efficacy, inconvenience, and fear of side effects. Other factors include forgetfulness, financial burden of treatment, lack of trust in the physician, dislike of prescribed medication, or lack of understanding of disease or treatment. Several interventions have been studied with the aim of improving adherence in atopic dermatitis-such as educational workshops for patients and caregivers, earlier follow-up visits, and text messages reminders-however, these are often limited by sample size and power. Further research is needed to study both specific patterns of nonadherence in atopic dermatitis, as well as methods to improve them.

Non-Systemic Medication for the Treatment of Prurigo Nodularis: A Systematic Review.

Prurigo nodularis (PN) is a skin disease characterized by firm, itchy, erythematous lesions. Treatment consists of systemic and non-systemic modes of therapy. Non-systemic forms of treatment are first-line and include topical corticosteroids, topical steroid-sparing agents, and phototherapy. The objective was to review the efficacy of non-systemic treatment used to treat PN. A systematic search was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered with PROSPERO (CRD42023412012). The search consisted of keywords and Medical Subject Heading (MeSH) terms and translated to Ovid MEDLINE, Embase, and Scopus. Google Scholar was also searched for the first 200 articles. Article quality of evidence was scored using GRADE criteria. The search yielded 1151 results; 37 met criteria for inclusion. There were 14 studies on phototherapy, and 11 studies on topical corticosteroids, most of which were also combined with topical antihistamines, antipruritics, and/or phototherapy. There were 2 studies each on topical antipruritics used in isolation, vitamin D analogues, and intralesional triamcinolone acetonide. There was 1 study each on topical pimecrolimus, tacrolimus, 2% dinitrochlorobenzene, cryotherapy, acupuncture, and the Paul Gerson Unna boot. Most were case reports and case series, although 2 randomized controlled trials on phototherapy and topical pimecrolimus were included. Corticosteroids had varying levels of positive response in patients and appeared more effective when used in combination or under occlusive dressing. Phototherapy is likely effective, but the risk of relapse is high. Cryotherapy may also be a lesion-directed agent to circumvent challenges to adherence and avoidance of systemic medication.

Biologics for Treatment of Pityriasis Rubra Pilaris: A Literature Review.

OBJECTIVE: To describe the published efficacy and adverse event rates associated with existing biologics for the treatment of pityriasis rubra pilaris (PRP). DATA SOURCES: A literature review using the PubMed database (January 1990-July 2023) was conducted. Multiple search combinations were conducted using "pityriasis rubra pilaris" and various biologics as keywords to identify relevant articles. STUDY SELECTION AND DATA EXTRACTION: Inclusion criteria included all study types that were published within the past 30 years in English and mentioned at least one biologic and PRP. A preliminary search yielded a total of 499 results. After screening using inclusion and exclusion criteria, 77 relevant articles (69 case reports, 5 case series, 2 clinical trials, and 1 retrospective analysis) were analyzed. DATA SYNTHESIS: TNF-α inhibitors have been evaluated and are effective in treating PRP. However, recent treatment with anti-interleukin (IL)-17 and anti-IL-23 therapies such as ustekinumab, secukinumab, and ixekizumab are emerging as new treatment options with a mean improvement in PRP Area and Severity Index scores, change in severity of erythema, scaling, and thickness of PRP lesions. From initial clinical trials, secukinumab and ixekizumab are promising treatment options for achieving remission. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review compares the efficacy for numerous biologics and a discussion to guide clinicians on benefits and risks in choosing a biologic for PRP patients. CONCLUSIONS: Biologics may be a favourable treatment option leading to greater patient adherence due to reduced dosing frequencies, improvement in quality of life, and reduction in frequency and severity of flares.

Overview of Dermatological Manifestations Associated with the COVID-19 Infection.

COVID-19 is an infectious disease caused by SARS-CoV-2 that is characterized by respiratory symptoms, fever, and chills.[1] While these systemic symptoms are widely known and well understood, there have also been reports of dermatological manifestations in patients with COVID-19. These manifestations include chilblain-like lesions, maculopapular lesions, urticarial lesions, necrosis, and other varicella-like exanthems.[2] The pathogenesis of these lesions are not well understood, but the procoagulant and pro-inflammatory state induced by COVID-19 infections may be contributing to varied cutaneous manifestations.[3] Drug interactions and concurrent hypersensitivity reactions have also been postulated.[4] This review aims to compile and analyze various retrospective studies and case reports to summarize the clinical presentation of dermatological lesions associated with COVID-19 infections and suggest further areas of research.

Homology-independent targeted insertion (HITI) enables guided CAR knock-in and efficient clinical scale CAR-T cell manufacturing.

BACKGROUND: Chimeric Antigen Receptor (CAR) T cells are now standard of care (SOC) for some patients with B cell and plasma cell malignancies and could disrupt the therapeutic landscape of solid tumors. However, access to CAR-T cells is not adequate to meet clinical needs, in part due to high cost and long lead times for manufacturing clinical grade virus. Non-viral site directed CAR integration can be accomplished using CRISPR/Cas9 and double-stranded DNA (dsDNA) or single-stranded DNA (ssDNA) via homology-directed repair (HDR), however yields with this approach have been limiting for clinical application (dsDNA) or access to large yields sufficient to meet the manufacturing demands outside early phase clinical trials is limited (ssDNA). METHODS: We applied homology-independent targeted insertion (HITI) or HDR using CRISPR/Cas9 and nanoplasmid DNA to insert an anti-GD2 CAR into the T cell receptor alpha constant (TRAC) locus and compared both targeted insertion strategies in our system. Next, we optimized post-HITI CRISPR EnrichMENT (CEMENT) to seamlessly integrate it into a 14-day process and compared our knock-in with viral transduced anti-GD2 CAR-T cells. Finally, we explored the off-target genomic toxicity of our genomic engineering approach. RESULTS: Here, we show that site directed CAR integration utilizing nanoplasmid DNA delivered via HITI provides high cell yields and highly functional cells. CEMENT enriched CAR T cells to approximately 80% purity, resulting in therapeutically relevant dose ranges of 5.5 × 108-3.6 × 109 CAR + T cells. CRISPR knock-in CAR-T cells were functionally comparable with viral transduced anti-GD2 CAR-T cells and did not show any evidence of off-target genomic toxicity. CONCLUSIONS: Our work provides a novel platform to perform guided CAR insertion into primary human T-cells using nanoplasmid DNA and holds the potential to increase access to CAR-T cell therapies.

CD22-directed CAR T-cell therapy induces complete remissions in CD19-directed CAR-refractory large B-cell lymphoma.

The prognosis of patients with large B-cell lymphoma (LBCL) that progresses after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first 3 consecutive patients with autologous CAR19-refractory LBCL who were treated with a single infusion of autologous 1 × 106 CAR+ T cells per kilogram targeting CD22 (CAR22) as part of a phase 1 dose-escalation study. CAR22 therapy was relatively well tolerated, without any observed nonhematologic adverse events higher than grade 2. After infusion, all 3 patients achieved complete remission, with all responses continuing at the time of last follow-up (mean, 7.8 months; range, 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range, 85.4-350 cells per microliter), and persisted beyond 3 months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA beyond 6 months after infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients in whom prior CAR T-cell therapies have failed. This trial is registered on clinicaltrials.gov as #NCT04088890.

Bromhidrosis treatment modalities: A literature review.

BACKGROUND: Treatment options for Bromhidrosis include botulinum toxin therapy, microwave-based therapy, laser therapy, and surgical intervention. Limited studies compare their efficacies. OBJECTIVE: The purpose of this literature review is to compare the efficacy and safety of these treatments for bromhidrosis. METHODS: A PubMed search included terms bromhidrosis and bromhidrosis AND treatment. RESULTS: A total of 25 articles were reviewed. Botulinum toxin therapy shows consistent benefit but requires repeated therapies. Microwave therapies have shown promising results but require larger cohort sizes with bromhidrosis. Similarly, laser therapy has shown promise with biopsy-proven results, but long-lasting effects remain unknown. Surgery has the best long-term prognosis, but the ideal surgical method remains unknown. LIMITATIONS: Each study varied in their treatment interval and method of assessing bromhidrosis, making direct comparisons difficult. CONCLUSIONS: Managing bromhidrosis requires shared decision making with the patient. Mild-to-moderate symptoms may be treated initially with botulinum toxin therapy. In cases that are refractory, laser therapy should be considered, as it is better studied than microwave therapy currently. Lastly, if the condition is severe and refractory to other options, surgery can be considered, although the ideal method remains unknown.