Pediatric cutaneous T-cell neoplasm and mimics with gamma-delta expression: Not always aggressive.

Pediatric cutaneous T-cell lymphoma with γδ immunophenotype is extremely rare. Only a few cases of γδ T-cell neoplasm have been reported in the literature, and therefore little is known whether γδ T-cell neoplasms in children are distinct from their adult counterparts with respect to the clinicopathological presentation, behavior, and prognosis. In this study, we demonstrate three unique pediatric cutaneous T-cell neoplasm and mimics with increased γδ T cells. All cases showed an indolent clinical course.

Durable immunity to EBV after rituximab and third-party LMP-specific T cells: a Children's Oncology Group study.

ABSTRACT: Posttransplant lymphoproliferative disease (PTLD) in pediatric solid organ transplant (SOT) recipients is characterized by uncontrolled proliferation of Epstein-Barr virus-infected (EBV+) B cells due to decreased immune function. This study evaluated the feasibility, safety, clinical and immunobiological outcomes in pediatric SOT recipients with PTLD treated with rituximab and third-party latent membrane protein-specific T cells (LMP-TCs). Newly diagnosed (ND) patients without complete response to rituximab and all patients with relapsed/refractory (R/R) disease received LMP-TCs. Suitable LMP-TC products were available for all eligible subjects. Thirteen of 15 patients who received LMP-TCs were treated within the prescribed 14-day time frame. LMP-TC therapy was generally well tolerated. Notable adverse events included 3 episodes of rejection in cardiac transplant recipients during LMP-TC therapy attributed to subtherapeutic immunosuppression and 1 episode of grade 3 cytokine release syndrome. Clinical outcomes were associated with disease severity. Overall response rate (ORR) after LMP-TC cycle 1 was 70% (7/10) for the ND cohort and 20% (1/5) for the R/R cohort. For all cohorts combined, the best ORR for LMP-TC cycles 1 and 2 was 53% and the 2-year overall survival was 70.7%. vßT-cell receptor sequencing showed persistence of adoptively transferred third-party LMP-TCs for up to 8 months in the ND cohort. This study establishes the feasibility of administering novel T-cell therapies in a cooperative group clinical trial and demonstrates the potential for positive outcomes without chemotherapy for ND patients with PTLD. This trial was registered at www.clinicaltrials.gov as #NCT02900976 and at the Children's Oncology Group as ANHL1522.

Mediport use as an acceptable standard for CAR T cell infusion.

Introduction: Mediport use as a clinical option for the administration of chimeric antigen receptor T cell (CAR T cell) therapy in patients with B-cell malignancies has yet to be standardized. Concern for mediport dislodgement, cell infiltration, and ineffective therapy delivery to systemic circulation has resulted in variable practice with intravenous administration of CAR T cell therapy. With CAR T cell commercialization, it is important to establish practice standards for CAR T cell delivery. We conducted a study to establish usage patterns of mediports in the clinical setting and provide a standard of care recommendation for mediport use as an acceptable form of access for CAR T cell infusions. Methods: In this retrospective cohort study, data on mediport use and infiltration rate was collected from a survey across 34 medical centers in the Pediatric Real-World CAR Consortium, capturing 504 CAR T cell infusion routes across 489 patients. Data represents the largest, and to our knowledge sole, report on clinical CAR T cell infusion practice patterns since FDA approval and CAR T cell commercialization in 2017. Results: Across 34 sites, all reported tunneled central venous catheters, including Broviac® and Hickman® catheters, as accepted standard venous options for CAR T cell infusion. Use of mediports as a standard clinical practice was reported in 29 of 34 sites (85%). Of 489 evaluable patients with reported route of CAR T cell infusion, 184 patients were infused using mediports, with no reported incidences of CAR T cell infiltration. Discussion/Conclusion: Based on current clinical practice, mediports are a commonly utilized form of access for CAR T cell therapy administration. These findings support the safe practice of mediport usage as an accepted standard line option for CAR T cell infusion.

Overcoming barriers to drug development and enrollment in clinical trials for adolescents and young adults with lymphoma.

Lymphoma is one of the most common cancers in adolescents and young adults, but historically, this population has had lower clinical trial enrollment and improvements in overall survival as compared to other age populations. There are multiple challenges that are unique to this population that have affected drug development and clinical trial enrollment. Our panel of experts have identified barriers, and in this review, we discuss current methods to address these barriers as well as potential solutions moving forward.

Diagnosis and management of post-transplant lymphoproliferative disease following solid organ transplantation in children, adolescents, and young adults.

Post-transplant Lymphoproliferative Disease (PTLD) remains a major complication of solid organ transplantation (SOT) in pediatric patients. The majority are Epstein-Barr Virus (EBV) driven CD20+ B-cell proliferations responsive to reduction to immunosuppression and anti-CD20 directed immunotherapy. This review focusses on the epidemiology, role of EBV, clinical presentation, current treatment strategies, adoptive immunotherapy and future research in EBV + PTLD in pediatric patients.

CD19 CAR-T cell therapy for relapsed or refractory diffuse large B cell lymphoma: Why does it fail?

Chimeric antigen receptor T (CAR-T) cell therapy is an effective treatment for relapsed or refractory diffuse large B cell lymphoma (DLBCL) with 3 CD19 targeting products now FDA-approved for this indication. However, up to 60% of patients ultimately progress or relapse following CAR-T cell therapy. Mechanisms of resistance to CAR-T cell therapy in patients with DLBCL are likely multifactorial and have yet to be fully elucidated. Determining patient, tumor and therapy-related factors that may predict an individual's response to CAR-T cell therapy requires ongoing analysis of data from clinical trials and real-world experience in this population. In this review we will discuss the factors identified to-date that may contribute to failure of CAR-T cell therapy in achieving durable remissions in patients with DLBCL.

EBV+ lymphoproliferative diseases: opportunities for leveraging EBV as a therapeutic target.

Epstein-Barr virus (EBV) is a ubiquitous human tumor virus, which contributes to the development of lymphoproliferative disease, most notably in patients with impaired immunity. EBV-associated lymphoproliferation is characterized by expression of latent EBV proteins and ranges in severity from a relatively benign proliferative response to aggressive malignant lymphomas. The presence of EBV can also serve as a unique target for directed therapies for the treatment of EBV lymphoproliferative diseases, including T cell-based immune therapies. In this review, we describe the EBV-associated lymphoproliferative diseases and particularly focus on the therapies that target EBV.

Tumor-associated antigen-specific T cells with nivolumab are safe and persist in vivo in relapsed/refractory Hodgkin lymphoma.

Hodgkin lymphoma (HL) Reed Sternberg cells express tumor-associated antigens (TAA) that are potential targets for cellular therapies. We recently demonstrated that TAA-specific T cells (TAA-Ts) targeting WT1, PRAME, and Survivin were safe and associated with prolonged time to progression in solid tumors. Hence, we evaluated whether TAA-Ts when given alone or with nivolumab were safe and could elicit antitumor effects in vivo in patients with relapsed/refractory (r/r) HL. Ten patients were infused with TAA-Ts (8 autologous and 2 allogeneic) for active HL (n = 8) or as adjuvant therapy after hematopoietic stem cell transplant (n = 2). Six patients received nivolumab priming before TAA-Ts and continued until disease progression or unacceptable toxicity. All 10 products recognized 1 or more TAAs and were polyfunctional. Patients were monitored for safety for 6 weeks after the TAA-Ts and for response until disease progression. The infusions were safe with no clear dose-limiting toxicities. Patients receiving TAA-Ts as adjuvant therapy remain in continued remission at 3+ years. Of the 8 patients with active disease, 1 patient had a complete response and 7 had stable disease at 3 months, 3 of whom remain with stable disease at 1 year. Antigen spreading and long-term persistence of TAA-Ts in vivo were observed in responding patients. Nivolumab priming impacted TAA-T recognition and persistence. In conclusion, treatment of patients with r/r HL with TAA-Ts alone or in combination with nivolumab was safe and produced promising results. This trial was registered at www.clinicaltrials.gov as #NCT022039303 and #NCT03843294.

Novel TCR-like CAR-T cells targeting an HLA∗0201-restricted SSX2 epitope display strong activity against acute myeloid leukemia.

The synovial sarcoma X breakpoint 2 (SSX2) belongs to a multigene family of cancer-testis antigens and can be found overexpressed in multiple malignancies. Its restricted expression in immune-privileged normal tissues suggest that SSX2 may be a relevant target antigen for chimeric antigen receptor (CAR) therapy. We have developed a T cell receptor (TCR)-like antibody (Fab/3) that binds SSX2 peptide 41-49 (KASEKIFYV) in the context of HLA-A∗-0201. The sequence of Fab/3 was utilized to engineer a CAR with the CD3 zeta intra-cellular domain along with either a CD28 or 4-1BB costimulatory endodomain. Human T cells from HLA-A2+ donors were transduced to mediate anti-tumor activity against acute myeloid leukemia (AML) tumor cells. Upon challenge with HLA-A2+/SSX2+ AML tumor cells, CAR-expressing T cells released interferon-γ and eliminated the tumor cells in a long-term co-culture assay. Using the HLA-A2+ T2 cell line, we demonstrated a strong specificity of the single-chain variable fragment (scFv) for SSX2 p41-49 and the closely related SSX3 p41-49, with no response against the others SSX-homologous peptides or unrelated homologous peptides. Since SSX3 has not been observed in tumor cells and expression cannot be induced by pharmacological intervention, SSX241-49 represents an attractive target for CAR-based cellular therapy to treat multiple types of cancer.

Flow-based analysis of cell division identifies highly active populations within plasma products during mixed lymphocyte cultures.

BACKGROUND: Leukoreduction to eliminate mononuclear cells within blood products is necessary to prevent graft-versus-host disease after transfusion. Published reports document low concentrations of mononuclear cells leftover in fresh-frozen plasma products, however the phenotype and the proliferative potential of these cells has not been tested. MATERIALS AND METHODS: We investigated residual cellular components contained within fresh and fresh-frozen plasma products and characterised their proliferative potential in co-cultures with unrelated allogeneic cells. We designed a flow-based assay to phenotype cells and quantify cell division by measuring the dilution of fluorescently labeled protein as cells divide. Leukocytes from consenting donors were purified from fresh liquid or fresh-frozen plasma units and cultured for three to seven days with unrelated irradiated allogeneic targets. RESULTS: We discovered a median of 1.6×107 viable lymphocytes were detectable in fresh plasma units after collection (n=8), comprised of a mixture of CD3+ CD8+ and CD3+ CD4+ cells. Furthermore, we identified a median of 8.4% of live CD3+ plasma lymphocytes divided as early as Day 4 when co-cultured with unrelated allogeneic cells, expanding to a median 88.8% by Day 7 (n=3). Although freezing the plasma product reduced the total number of viable leukocyte cells down to 2.3×105 (n=10), residual naive CD3+ cells were viable and demonstrated division through Day 7 of co-culture. DISCUSSION: The evidence of viable proliferative lymphocytes in fresh and fresh-frozen plasma products derived from centrifugation suggests that additional leukoreduction measures should be investigated to fully eradicate reactive lymphocytes from centrifuged plasma products.

T-cell therapies for T-cell lymphoma.

T-cell lymphomas represent a subpopulation of non-Hodgkin lymphomas with poor outcomes when treated with conventional chemotherapy. A variety of novel agents have been introduced as new treatment strategies either as first-line treatment or in conjunction with chemotherapy. Immunotherapy has been demonstrated to be a promising area for new therapeutics, including monoclonal antibodies and adoptive cellular therapeutics. T-cell therapeutics have been shown to have significant success in the treatment of B-cell malignancies and are rapidly expanding as potential treatment options for other cancers including T-cell lymphomas. Although treating T-cell lymphomas with T-cell therapeutics has unique challenges, multiple targets are currently being studied both preclinically and in clinical trials.

A 17-Year-Old Girl With Weight Loss and Elevated Inflammatory Markers.

A 17-year-old girl presented to her primary care physician with a history of unintentional weight loss and vague sensory symptoms, including tingling of her lower extremities. She had a nonrevealing neurology workup and a largely normal rheumatology workup apart from mild elevation in her inflammatory markers. She also had a nonfocal examination apart from a posterior cervical lymph node (2 × 1 cm). Given that she was well appearing, with a nonfocal examination and only mild laboratory abnormalities, she was told to follow-up with rheumatology in 3 months. Around that time, she re-presented to her medical home for a well-child visit, during which she was noted to have continued weight loss, now amounting to 17 lb in 1 year, and marked further elevation in her inflammatory markers. Her laboratory results were also significant for a profound microcytic anemia requiring inpatient admission for blood transfusion. During her admission, she was seen by the rheumatology, gastroenterology, and oncology subspecialty teams. Despite imaging studies and extensive laboratory workup, there was no unifying diagnosis at the time of her hospital discharge. Ultimately, an outpatient imaging study revealed the etiology.

Children With Medical Complexity: A Web-Based Multimedia Curriculum Assessing Pediatric Residents Across North America.

OBJECTIVE: No standardized curricula exist for training residents in the special needs of children with medical complexity. We assessed resident satisfaction, knowledge, and behavior after implementing a novel online curriculum composed of multimedia modules on care of children with medical complexity utilizing virtual simulation. METHODS: We conducted a randomized controlled trial of residents across North America. A Web-based curriculum of 6 self-paced, interactive, multimedia modules was developed. Readings for each topic served as the control curriculum. Residents were randomized to 1 of 2 groups, each completing 3 modules and 3 sets of readings that were mutually exclusive. Outcomes included resident scores on satisfaction, knowledge-based assessments, and virtual simulation activities. RESULTS: Four hundred forty-two residents from 56 training programs enrolled in the curriculum, 229 of whom completed it and were included in the analysis. Subjects were more likely to report comfort with all topics if they reviewed modules compared to readings (P ≤ .01 for all 6 topics). Posttest knowledge scores were significantly higher than pretest scores overall (mean increase in score 17.7%; 95% confidence interval 16.0, 19.4), and the mean pre-post score increase for modules was significantly higher than readings (20.9% vs 15.4%, P < .001). Mean scores on the verbal handoff virtual simulation increased by 1.1 points (95% confidence interval 0.2, 2.0, P = .02). There were no significant differences found in pre-post performance for the device-related emergency virtual simulation. CONCLUSIONS: There was high satisfaction, significant knowledge acquisition, and specific behavior change after participating in this innovative online curriculum. This is the first multisite, randomized trial assessing satisfaction, knowledge impact, and behavior change in a virtually simulated environment with pediatric trainees.

The Handy Eye Check: a mobile medical application to test visual acuity in children.

PURPOSE: To compare visual acuity results obtained with the Handy Eye Chart to results obtained using the Handy Eye Check, a mobile medical application that electronically presents isolated Handy Eye Chart optotypes according the Amblyopia Treatment Study (ATS) protocol. METHODS: Consecutive patients 6-18 years of age presenting for eye examinations between May 30, 2012, and June 26, 2012, were invited to participate. Monocular visual acuity testing was performed on the subject's poorer-seeing eye using both the Handy Eye Check and the Handy Eye Chart under the same conditions. Visual acuity was first tested using the mobile application, then using the chart, followed by repeated application testing. Patients were excluded if they were unable to undergo the required visual acuity testing or if visual acuity in the worse-seeing eye was less than 20/200 (for validity testing, but not reliability testing). RESULTS: There was a strong linear correlation (r = 0.92) and a mean difference in acuity of -0.005 logMAR, or less than one letter (95% CI, -0.03 to 0.02), between the two tests. The 95% limits of agreement were ± 2 lines. Test-retest reliability was high, with 81% of retest scores within 0.1 logMAR (5 letters) and 100% within 0.2 logMAR (10 letters), an intraclass correlation coefficient of 0.93, and a standard error of measurement of 0.08. CONCLUSIONS: The Handy Eye Check mobile application compares similarly to the Handy Eye Chart as a valid and reliable test of visual acuity in children age 6-18 years.