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Radiation and Modulation of the Tumor Immune Microenvironment in Non-Small Cell Lung Cancer

Semin Radiat Oncol

2021 Jing Zeng; Stephanie Schaub; Ramesh Rengan

Immune checkpoint inhibitors are approved for a variety of indications for locally advanced and metastatic non-small cell lung cancer (NSCLC), and trials are ongoing in the early-stage setting. There is an unmet need to understand which patients may derive benefit from immunotherapies and how to harness combined modality therapies to improve overall response rates and durability. Here, we review studies from the bench-to-bedside to examine the role of radiation therapy (RT) on the tumor immune microenvironment in NSCLC with an eye toward augmenting antitumor immunity. Together, these data provide a foundation for developing future clinical trials harnessing RT to augment antitumor immunity and highlight the need for correlative translational studies to directly characterize the impact of RT on the human NSCLC tumor immune microenvironment.

Dynamics of thymus function and T cell receptor repertoire breadth in health and disease

Semin Immunopathol

2021 David Granadier; Lorenzo Iovino; Jarrod Dudakov; Sinéad Kinsella

T cell recognition of unknown antigens relies on the tremendous diversity of the T cell receptor (TCR) repertoire; generation of which can only occur in the thymus. TCR repertoire breadth is thus critical for not only coordinating the adaptive response against pathogens but also for mounting a response against malignancies. However, thymic function is exquisitely sensitive to negative stimuli, which can come in the form of acute insult, such as that caused by stress, infection, or common cancer therapies; or chronic damage such as the progressive decline in thymic function with age. Whether it be prolonged T cell deficiency after hematopoietic cell transplantation (HCT) or constriction in the breadth of the peripheral TCR repertoire with age; these insults result in poor adaptive immune responses. In this review, we will discuss the importance of thymic function for generation of the TCR repertoire and how acute and chronic thymic damage influences immune health. We will also discuss methods that are used to measure thymic function in patients and strategies that have been developed to boost thymic function.

Targeting the membrane-proximal C2-set domain of CD33 for improved CD33-directed immunotherapy


2021 Colin Correnti; Salvatore Fiorenza; Cameron Turtle; Roland Walter; George Laszlo; Eliotte Garling; Margaret Lunn; Olivia Bates; Colin Godwin; Olivier Humbert; Hans-Peter Kiem; Benjamin Hoffstrom; Tinhdoan Phi

There is increasing interest in targeting CD33 in malignant and non-malignant disorders. In acute myeloid leukemia, longer survival with the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO) validates this strategy. Still, GO benefits only some patients, prompting efforts to develop more potent CD33-directed therapeutics. As one limitation, CD33 antibodies typically recognize the membrane-distal V-set domain. Using various artificial CD33 proteins, in which this domain was differentially positioned within the extracellular portion of the molecule, we tested whether targeting membrane-proximal epitopes enhances the effector functions of CD33 antibody-based therapeutics. Consistent with this idea, a CD33V-set/CD3 bispecific antibody (BsAb) and CD33V-set-directed chimeric antigen receptor (CAR)-modified T cells elicited substantially greater cytotoxicity against cells expressing a CD33 variant lacking the entire C2-set domain than cells expressing full-length CD33, whereas cytotoxic effects induced by GO were independent of the position of the V-set domain. We therefore raised murine and human antibodies against the C2-set domain of human CD33 and identified antibodies that bound CD33 regardless of the presence/absence of the V-set domain ("CD33PAN antibodies"). These antibodies internalized when bound to CD33 and, as CD33PAN/CD3 BsAb, had potent cytolytic effects against CD33+ cells. Together, our data provide the rationale for further development of CD33PAN antibody-based therapeutics.

DAS181 Treatment of Severe Lower Respiratory Tract Parainfluenza Virus Infection in Immunocompromised Patients: A Phase 2 Randomized, Placebo-Controlled Study

Clin Infect Dis

2021 Michael Boeckh

BACKGROUND: There are no antiviral therapies for Parainfluenza virus (PIV) infections. DAS181, a sialidase fusion protein, has demonstrated activity in in vitro and in animal models of PIV. METHODS: Adult immunocompromised patients diagnosed with PIV lower respiratory tract infection (LRTI) who required oxygen supplementation were randomized 2:1 to nebulized DAS181 (4.5mg/day) or matching placebo for up to 10 days. Randomization was stratified by need for mechanical ventilation (MV) or supplemental oxygen (SO). The primary endpoint was the proportion of patients reaching clinical stability survival (CSS) defined as returning to breathing room air (RTRA), normalization of vital signs for at least 24 hours, and survival up to day 45 from enrollment. RESULTS: A total of 111 patients were randomized to DAS181 (n=74) or placebo (n=37). CSS was achieved by 45.0% DAS181 treated patients in the SO stratum compared with 31.0% for placebo (p=0.15), while patients on MV had no benefit from DAS181. The proportion of patients achieving RTRA was numerically higher for SO stratum DAS181 patients (51.7%) compared with Placebo (34.5%) at Day 28 (p=0.17). In a post-hoc analysis of solid organ transplant, hematopoietic cell transplantation within one year, or chemotherapy within one year, more SO stratum patients achieved RTRA on DAS181 (51.8%) when compared to placebo (15.8%) by day 28 (p=0.012). CONCLUSION: The primary endpoint was not met, but post-hoc analysis of the RTRA component suggests DAS181 may have clinical activity in improving oxygenation in select severely immunocompromised patients with PIV LRTI who are not on mechanical ventilation.

A phase 2b study to evaluate the safety and efficacy of VRC01 broadly neutralizing monoclonal antibody in reducing acquisition of HIV-1 infection in women in sub-Saharan Africa: baseline findings

J Acquir Immune Defic Syndr

2021 Kagisho Baepanye; Larry Corey; Michal Juraska; Erika Rudnicki; Carissa Karg; Nandisile Luthuli; Maurine Miner; Maija Anderson; John Hural; Michelle Karuna; Nidhi Kochar; India Tindale; Deborah Donnell; Kyle Marshall; Simbarashe Takuva

BACKGROUND: HIV Vaccine Trials Network (HVTN) 703/HIV Prevention Trials Network (HPTN) 081 is a phase 2b randomized, double-blind placebo-controlled trial to assess the safety and efficacy of passively infused monoclonal antibody (mAb) VRC01 in preventing HIV acquisition in heterosexual women between the ages of 18 and 50 at risk of HIV. Participants were enrolled at 20 sites in Botswana, Kenya, Malawi, Mozambique, South Africa, Tanzania and Zimbabwe. It is one of two Antibody Mediated Prevention (AMP) efficacy trials, with HVTN 704/HPTN 085, evaluating VRC01 for HIV prevention. METHODS: Intense community engagement was utilized to optimize participant recruitment and retention. Participants were randomly assigned to receive intravenous (IV) VRC01 10 mg/kg, VRC01 30 mg/kg, or placebo in a 1:1:1 ratio. Infusions were given every eight weeks with a total of 10 infusions and 104 weeks of follow-up after the first infusion. RESULTS: Between May 2016 and September 2018, 1924 women from sub-Saharan Africa were enrolled. The median age was 26 (IQR: 22-30) and 98.9% were Black. Sexually transmitted infection prevalence at enrollment included chlamydia (16.9%), trichomonas (7.2%), gonorrhea (5.7%) and syphilis (2.2%). External condoms (83.2%) and injectable contraceptives (61.1%) were the methods of contraception most frequently used by participants. In total, through April 3, 2020, 38,490 clinic visits were completed with a retention rate of 96% and 16,807 infusions administered with an adherence rate of 98%. CONCLUSIONS: This proof-of-concept, large-scale mAb study demonstrates the feasibility of conducting complex trials involving IV infusions in high-incidence populations in sub-Saharan Africa.

Feasibility and Successful Enrollment in a Proof-of-Concept HIV Prevention Trial of VRC01, a Broadly Neutralizing HIV-1 Monoclonal Antibody

J Acquir Immune Defic Syndr

2021 Maija Anderson; Gail Broder; India Tindale; Allan DeCamp; Peter Gilbert; John Hural; Carissa Karg; Michelle Karuna; Larry Corey; Maurine Miner; Robert De La Grecca; Nidhi Kochar; Erika Rudnicki

BACKGROUND: The Antibody Mediated Prevention (AMP) trials (HVTN 704/HPTN 085 & HVTN 703/HPTN 081) are the first efficacy trials to evaluate whether VRC01, a broadly neutralizing monoclonal antibody (mAb) targeting the CD4 binding site of the HIV envelope protein, prevents sexual transmission of HIV-1. HVTN 704/HPTN 085 enrolled 2,701 cisgender men and transgender (TG) individuals who have sex with men at 26 sites in Brazil, Peru, Switzerland and the United States. METHODS: Participants were recruited and retained through early, extensive community engagement. Eligible participants were randomized 1:1:1 to 10 mg/kg or 30 mg/kg of VRC01 or saline placebo. Visits occurred monthly, with intravenous (IV) infusions every 8 weeks over 2 years, for a total of ten infusions. Participants were followed for 104 weeks after first infusion. RESULTS: The median HVTN 704/HPTN 085 participant age was 28; 99% were assigned male sex; 90% identified as cisgender male, 5% as TG female and the remaining as other genders. Thirty-two percent were White, 15% Black and 57% Hispanic/Latinx. Twenty-eight percent had a sexually transmitted infection at enrollment. Over 23,000 infusions were administered with no serious IV administration complications. Overall retention and adherence to the study schedule exceeded 90%, and the drop-out rate was below 10% annually (7.3 per 100-person years) through Week 80, the last visit for the primary endpoint. CONCLUSIONS: HVTN 704/HPTN 085 exceeded accrual and retention expectations. With exceptional safety of IV administration and operational feasibility, it paves the way for future large-scale mAb trials for HIV prevention and/or treatment.

Predicting severe toxicities with intensive induction chemotherapy for adult acute myeloid leukemia: analysis of SWOG Cancer Research Network trials S0106 and S1203

Leuk Lymphoma

2021 Anna Moseley; Fred Appelbaum; Roland Walter; Megan Othus


Pembrolizumab in mycosis fungoides with PD-L1 structural variants

Blood Adv

2021 Steven Fling; Nirasha Ramchurren; Srinivas Ramachandran; Martin Cheever


Evaluating Specimen Quality and Results from a Community-Wide, Home-Based Respiratory Surveillance Study

J Clin Microbiol

2021 Jover Lee; Trevor Bedford; Michael Boeckh; Janet Englund; Debbie Nickerson; Mikaela Ilcisin; Thomas Sibley; Matthew Thompson; Kairsten Fay; Lea Starita

Introduction. While influenza and other respiratory pathogens cause significant morbidity and mortality, the community-based burden of these infections remains incompletely understood. The development of novel methods to detect respiratory infections is essential for mitigating epidemics and developing pandemic-preparedness infrastructure.Methods. From October 2019 to March 2020, we conducted a home-based cross-sectional study in the greater Seattle area, utilizing electronic consent and data collection instruments. Participants received nasal swab collection kits via rapid delivery within 24 hours of self-reporting respiratory symptoms. Samples were returned to the laboratory and were screened for 26 respiratory pathogens and a housekeeping gene. Participant data were recorded via online survey at the time of sample collection and one week later.Results. Of the 4,572 consented participants, 4,359 (95.3%) received a home swab kit, and 3,648 (83.7%) returned a nasal specimen for respiratory pathogen screening. The 3,638 testable samples had a mean RNase P CRT value of 19.0 (SD: 3.4) and 1,232 (33.9%) samples had positive results for one or more pathogens, including 645 (17.7%) influenza-positive specimens. Among the testable samples, the median time between shipment of the home swab kit and completion of laboratory testing was 8 days [IQR: 7.0-14.0]. A single adverse event occurred and did not cause long-term effects or require medical attention.Discussion. Home-based surveillance using online participant enrollment and specimen self-collection is a safe and feasible method for community-level monitoring of influenza and other respiratory pathogens, which can readily be adapted for use during pandemics.

A clinical perspective on plasma cell leukemia; current status and future directions

Blood Cancer J

2021 Leona Holmberg; Sherilyn Tuazon

Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder with a guarded prognosis. The diagnosis is confirmed when peripheral blood plasma cells (PCs) exceed 20% of white blood cells or 2000/μL. Emerging data demonstrates that patients with lower levels of circulating (PCs) have the same adverse prognosis, challenging the clinical disease definition, but supporting the adverse impact of circulating PCs. The cornerstone of treatment consists of combination therapy incorporating a proteasome inhibitor, an immunomodulatory agent, steroids, and/or anthracyclines and alkylators as part of more-intensive chemotherapy, followed by consolidative autologous hematopoietic cell transplantation in eligible patients and then maintenance therapy. Monoclonal antibodies are also currently being evaluated in this setting with a strong rationale for their use based on their activity in multiple myeloma (MM). Due to limited therapeutic studies specifically evaluating pPCL, patients with pPCL should be considered for clinical trials. In contrast to MM, the outcomes of patients with pPCL have only modestly improved with novel therapies, and secondary PCL arising from MM in particular is associated with a dismal outlook. Newer drug combinations, immunotherapy, and cellular therapy are under investigation, and these approaches hopefully will demonstrate efficacy to improve the prognosis of pPCL.