Interleukin-7 (IL-7) is a homeostatic cytokine for resting T cells with increasing serum and tissue levels during T cell depletion. In preclinical studies, IL-7 therapy exerts marked stimulating effects on T cell immune reconstitution in mice and primates. First-in-humanclinical studies of recombinant human IL-7 (rhIL-7) provided the opportunity to investigate the effects of IL-7 therapy on lymphocytes in vivo. rhIL-7 induced in vivo T cell cycling, bcl-2 up-regulation, and a sustained increase in peripheral blood CD4 + and CD8 + T cells. This T cell expansion caused a signifi cant broadening of circulating T cell receptor (TCR) repertoire diversity independent of the subjects ' age as naive T cells, including recent thymic emigrants (RTEs), expanded preferentially, whereas the proportions of regulatory T (T reg) cells and senescent CD8 + effectors diminished. The resulting composition of the circulating T cell pool more closely resembled that seen earlier in life. This profi le, distinctive among cytokines under clinical development, suggests that rhIL-7 therapy could enhance and broaden immune responses, particularly in individuals with limited naive T cells and diminished TCR repertoire diversity, as occurs after physiological (age), pathological (human immunodefi ciency virus), or iatrogenic (chemotherapy) lymphocyte depletion. . Effects of rhIL-7 therapy on circulating T cells and spleen. rhIL-7 was administered every other day on day 1 -14 (8 injections, indicated by tick marks on X axis), at 4 dose levels: 3 μ g/kg/d (dashed line with ᭹ ; n = 3); 10 μ g/kg/d (dotted line with ᭝ ; n = 3); 30 μ g/kg/d (dashed line with ٗ ; n = 5); and 60 μ g/kg/d (solid line with ᭺ ; n = 4). Mean value for each cohort ( ± the SEM) are plotted at the indicated time points. (A) The absolute lymphocyte count from complete blood counts (left) and fl ow cytometry -based frequency were used to determine circulating absolute CD3 + / CD4 + and CD3 + /CD8 + counts, absolute numbers ± the SEM (bottom graphs), and percent change in absolute numbers over baseline (top graphs) of the respective subsets shown on day 1 (total lymphocytes only), 7, 14, 21, and 28 for all treated subjects, as well as day 55 -90 for subjects treated with 30 or 60 μ g/kg/d. Baseline values represent the mean of four separate analyses performed in each subject within 2 wk before initiation of rhIL-7 therapy. (B) Spleen size: bidimensional product by CT scan obtained at the time points shown; percent changes from the pretherapy scan are plotted. (C -F ) Baseline (1 value obtained on day 0) and day 7, 14, 21, and 28 data points were generated for CD3 + /CD4 + (left) and CD3 + /CD8 + subsets (right). augments antitumor responses, leading to improved survival when combined with antitumor vaccines ( 21,22 ). The capacity for supranormal levels of IL-7 to augment T cell cycling in response to antigens with low affi nity for the TCR appears largely responsible for homeostatic peripheral expansion, which involves increased T cell proliferation to self-antigens during...

PV701 warrants further study as a novel therapeutic agent for cancer patients.

Background Tocilizumab, a monoclonal antibody directed against the interleukin-6 receptor, has been proposed to mitigate the cytokine storm syndrome associated with severe COVID-19. We aimed to investigate the association between tocilizumab exposure and hospital-related mortality among patients requiring intensive care unit (ICU) support for COVID-19. Methods We did a retrospective observational cohort study at 13 hospitals within the Hackensack Meridian Health network (NJ, USA). We included patients (aged ≥18 years) with laboratory-confirmed COVID-19 who needed support in the ICU. We obtained data from a prospective observational database and compared outcomes in patients who received tocilizumab with those who did not. We applied a multivariable Cox model with propensity score matching to reduce confounding effects. The primary endpoint was hospital-related mortality. The prospective observational database is registered on ClinicalTrials.gov , NCT04347993 . Findings Between March 1 and April 22, 2020, 764 patients with COVID-19 required support in the ICU, of whom 210 (27%) received tocilizumab. Factors associated with receiving tocilizumab were patients' age, gender, renal function, and treatment location. 630 patients were included in the propensity score-matched population, of whom 210 received tocilizumab and 420 did not receive tocilizumab. 358 (57%) of 630 patients died, 102 (49%) who received tocilizumab and 256 (61%) who did not receive tocilizumab. Overall median survival from time of admission was not reached (95% CI 23 days–not reached) among patients receiving tocilizumab and was 19 days (16–26) for those who did not receive tocilizumab (hazard ratio [HR] 0·71, 95% CI 0·56–0·89; p=0·0027). In the primary multivariable Cox regression analysis with propensity matching, an association was noted between receiving tocilizumab and decreased hospital-related mortality (HR 0·64, 95% CI 0·47–0·87; p=0·0040). Similar associations with tocilizumab were noted among subgroups requiring mechanical ventilatory support and with baseline C-reactive protein of 15 mg/dL or higher. Interpretation In this observational study, patients with COVID-19 requiring ICU support who received tocilizumab had reduced mortality. Results of ongoing randomised controlled trials are awaited. Funding None.

MDS is a common hematologic malignancy of the elderly, which places patients at risk for comorbid conditions. Transfusion dependency identifies patients with MDS at additional increased risk of organ impairment and shortened survival.

In this article, we report on 904 patients undergoing transplantation for follicular lymphoma. A total of 176 (19%) received allogeneic, 131 (14%) received purged autologous, and 597 (67%) received unpurged autologous transplants. Five-year treatment-related mortality (TRM) rates were 30%, 14%, and 8% and 5-year recurrence rates were 21%, 43%, and 58% after allotransplantation, purged autotransplantation, and unpurged autotransplantation, respectively. In multivariate analyses, allotransplantation had higher TRM and lower disease recurrence. Purged autotransplantation had a 26% lower recurrence risk than unpurged autotransplantation. Five-year probabilities of survival were 51%, 62%, and 55% after allogeneic, purged autotransplantation, and unpurged autotransplantation, respectively. Advanced age, prolonged interval from diagnosis to transplantation, high lactate dehydrogenase (LDH), refractory disease, bone marrow involvement, low performance scores, and transplantation between 1990 and 1993 were associated with adverse outcomes. Total body irradiation was associated with higher TRM but lower recurrence. There was no association between acute or chronic graft-versus-host disease and recurrence after allotransplantation. We conclude that both allogeneic and autologous transplantation can induce durable remissions. There may be a benefit to graft purging in autologous transplantation. The decreased recurrence after allotransplantation is offset by increased TRM. We did not detect a correlation between graftversus-host disease (GVHD) and recurrence. Finally, outcomes of transplantation for follicular lymphoma show improvement over the past decade.

Purpose: Interleukin-7 (IL-7) has critical and nonredundant roles in T-cell development, hematopoiesis, and postdevelopmental immune functions as a prototypic homeostatic cytokine. Based on a large body of preclinical evidence, it may have multiple therapeutic applications in immunodeficiency states, either physiologic (immunosenescence), pathologic (HIV), or iatrogenic (postchemotherapy and posthematopoietic stem cell transplant), and may have roles in immune reconstitution or enhancement of immunotherapy. We report here on the toxicity and biological activity of recombinant human IL-7 (rhIL-7) in humans.Design: Subjects with incurable malignancy received rhIL-7 subcutaneously every other day for 2 weeks in a phase I interpatient dose escalation study (3, 10, 30, and 60 μg/kg/dose). The objectives were safety and dose-limiting toxicity determination, identification of a range of biologically active doses, and characterization of biological and, possibly, antitumor effects.Results: Mild to moderate constitutional symptoms, reversible spleen and lymph node enlargement, and marked increase in peripheral CD3 + , CD4 + , and CD8 + lymphocytes were seen in a dose-dependent and age-independent manner in all subjects receiving ≥10 μg/kg/dose, resulting in a rejuvenated circulating T-cell profile, resembling that seen earlier in life. In some subjects, rhIL-7 induced in the bone marrow a marked, transient polyclonal proliferation of pre-B cells showing a spectrum of maturation as well as an increase in circulating transitional B cells. Conclusion: This study shows the potent biological activity of rhIL-7 in humans over a well-tolerated dose range and allows further exploration of its possible therapeutic applications.

High-dose chemotherapy and autologous hematopoietic stem-cell transplantation should be considered for patients with diffuse aggressive NHL who never achieve a complete remission but who are still chemotherapy-sensitive and are otherwise transplant candidates.

Genomic testing presents multiple logistical challenges for the community-based oncologist, including coordination of sample handling, long turnaround times, test reimbursement, access to targeted therapies, insufficient tissue, and patient harm from the repeat biopsies necessary if the tissue sample is insufficient. Opportunities exist for improvement in guideline adherence, possibly through new technologies such as "liquid biopsies," which obviates the need tissue biopsy samples in select settings.