Virologic effects of broadly neutralizing antibodies VRC01LS and VRC07-523LS on chronic HIV-1 infection

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Abstract

BACKGROUND HIV-1–specific broadly neutralizing monoclonal antibodies (bNAbs) have emerged as promising interventions with the potential to effectively treat and prevent HIV-1 infections. We conducted a phase I clinical trial evaluating the potent CD4-binding site–specific (CD4bs-specific) bNAbs VRC01LS and VRC07-523LS in people with HIV-1 (PWH) not receiving antiretroviral therapy (ART).METHODS Participants received a single intravenous 40 mg/kg dose of either VRC01LS (n = 7) or VRC07-523LS (n = 9) and did not initiate ART for a minimum of 14 days. The primary study objective was to evaluate safety and tolerability; the secondary study objectives were to evaluate pharmacokinetics (PK) and the impact of administered bNAbs on viral loads (VL) and CD4+ T cell counts in the absence of ART.RESULTS This trial enrolled 16 PWH aged 20 to 57 years. Both bNAbs were safe and well tolerated. Mild local reactogenicity was only reported in participants who received VRC07-523LS, while both bNAbs were associated with mild systemic symptoms. Maximum serum concentrations (Cmax) following VRC01LS or VRC07-523LS were 1,566 ± 316 and 1,295 ± 376 μg/mL, respectively. VRC07-523LS administration significantly decreased VL in 8 out of 9 participants, with an average decline of 1.7 ± 0.8 log10 copies/mL within 14 days after administration. In contrast, VRC01LS administration resulted in a smaller average decline (0.8 ± 0.8 log10 copies/mL), and 3 out of 7 participants showedno change in VL. Postinfusion maximum decline in VL correlated with post hoc baseline in vitro viral susceptibility results for both bNAbs.CONCLUSION The results of this trial support inclusion of potent CD4bs-specific bNAbs, such as VRC07-523LS, into next-generation treatment regimens for HIV-1.TRIAL REGISTRATION ClinicalTrials.gov NCT02840474.FUNDING National Institute of Allergy and Infectious Diseases (NIAID)/NIH (grants UM1 AI068634, UM1 AI068636, UM1 AI106701, UM1AI069424, UM1AI069501, UM1AI69415, UM1AI069534, UM1AI69494); the Intramural Research Program of the NIAID/NIH; National Center for Advancing Translational Sciences/NIH (grants UM1TR004548, UL1TR001881, and UL1TR001878); and the National Cancer Institute/NIH (contract 75N91019D00024).

Authors

Myra Happe, Rebecca M. Lynch, Carl J. Fichtenbaum, Sonya L. Heath, Susan L. Koletar, Raphael J. Landovitz, Rachel M. Presti, Jorge L. Santana-Bagur, Randall L. Tressler, LaSonji A. Holman, Laura Novik, Jhoanna C. Roa, Ro Shauna Rothwell, Larisa Strom, Jing Wang, Zonghui Hu, Michelle Conan-Cibotti, Anjali M. Bhatnagar, Bridget Dwyer, Sung Hee Ko, Frida Belinky, Aryan M. Namboodiri, Janardan P. Pandey, Robin Carroll, Manjula Basappa, Leonid Serebryannyy, Sandeep R. Narpala, Bob C. Lin, Adrian B. McDermott, Eli A. Boritz, Edmund V. Capparelli, Emily E. Coates, Richard A. Koup, Julie E. Ledgerwood, John R. Mascola, Grace L. Chen, Pablo Tebas, the VRC 607/A5378 Study Team

First-in-human trial of engineered NK cells in lung cancer refractory to immune checkpoint inhibitors

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BACKGROUND. Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality necessitating the exploration of alternate therapeutic approaches. Tumor reactive or activated-by-cytokine killers (TRACK) are PD-L1+ highly cytolytic natural killer (NK) cells derived from umbilical cord blood NK cells and engineered to express soluble IL15 (sIL15), showing promise in preclinical studies against NSCLC. METHODS. We assessed safety, persistence, homing and cytotoxic activity in six patients with advanced, refractory, and progressing NSCLC who received a low dose of unmatched, allogeneic, off-the-shelf sIL15_TRACK NK cells. We evaluated NK cell presence and persistence with droplet digital (dd) PCR, flow cytometry, and immunofluorescent staining. RESULTS. sIL15_TRACK NK cells had peak measurements at one hour and became undetectable four hours after each in fusion. Cognate ligands to activating NK cell receptors were found in NSCLC. sIL15_TRACK NK cells were observed in a lung tumor biopsy seven days after the final infusion, confirming their sustainment and tumor-homing ability. They retained cytolytic function following isolation from the lung tumor. Three out of six patients achieved disease stabilization on repeat imaging, while the others progressed. CONCLUSION. Unmatched, allogeneic, cryopreserved, off-the-shelf sIL15_TRACK NK cells express activating receptors, home to tumor sites that express their cognate ligands, and retain cytolytic activity after infusion, underscoring their potential as a therapeutic approach in solid tumors. At low doses, the therapy was safely administered and showed preliminary evidence of activity in three of six patients with advanced and progressive NSCLC. Additional dose escalation cohorts and co-administration with atezolizumab are planned. TRIAL REGISTRATION. ClinicalTrials.gov NCT05334329 FUNDING. Funding was provided by CytoImmune Therapeutics; CA266457; CA033572; CA210087.

Authors

Miguel A. Villalona-Calero, Lei Tian, Xiaochen Li, Joycelynne M. Palmer, Claudia Aceves, Hans Meisen, Catherine Cortez, Timothy W. Synold, Colt Egelston, Jeffrey VanDeusen, Ivone Bruno, Lei Zhang, Eliezer Romeu-Bonilla, Omer Butt, Stephen J. Forman, Michael A. Caligiuri, Jianhua Yu

A randomized, double-blind, placebo controlled trial of IL-7 in critically ill COVID-19 patients

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BACKGROUND. Lymphopenia and failure of lymphocytes to mount an early IFN-γ response correlate with increased mortality in COVID-19. Given the essential role of CD4 helper and CD8 cytotoxic cells in eliminating viral pathogens, this profound loss in lymphocytes may impair patients’ ability to eliminate the virus. IL-7 is a pleiotropic cytokine that is obligatory for lymphocyte survival and optimal function. METHODS. We conducted a prospective, double-blind, randomized, placebo-controlled trial of CYT107, recombinant human IL-7, in 109 critically-ill lymphopenic COVID-19 patients. The primary endpoint was to assess CYT107’s effect on lymphocyte recovery with secondary clinical endpoints including safety, ICU and hospital length-of-stay, incidence of secondary infections, and mortality. RESULTS. CYT107 was well-tolerated without precipitating a cytokine storm or worsening pulmonary function. Absolute lymphocyte counts increased in both groups without significant difference between CYT107 and placebo. COVID-19 patients receiving CYT107 but not concomitant antiviral medications, known inducers of lymphopenia, had a final lymphocyte count that was 43% greater than placebo (p=0.067). There were significantly fewer treatment-emergent adverse events in CYT107 versus placebo-treated patients (p<0.001), consistent with a beneficial drug effect. Importantly, CYT107 treated patients had 44% fewer hospital-acquired infections versus placebo-treated patients (p=0.014). CONCLUSIONS. Given that hospital-acquired infections are responsible for a large percentage of COVID-19 deaths, this effect of CYT107 to decrease nosocomial infections could substantially reduce late morbidity and mortality in this highly lethal disease. The strong safety profile of CYT107 and its excellent tolerability provide support for trials of CYT107 in other potential pandemic respiratory viral infections. TRIAL REGISTRATION. NCT04379076, NCT04426201, NCT04442178, NCT04407689; NCT04927169

Authors

Manu Shankar-Hari, Bruno Francois, Kenneth E. Remy, Cristina Gutierrez, Stephen Pastores, Thomas Daix, Robin Jeannet, Jane Blood, Andrew H. Walton, Reinaldo Salomao, Georg Auzinger, David Striker, Robert S. Martin, Nitin J. Anand, James Bosanquet, Teresa Blood, Scott Brakenridge, Lyle L. Moldawer, Vidula Vachharajani, Cassian Yee, Felipe Dal-Pizzol, Michel Morre, Frederique Berbille, Marcel van den Brink, Richard Hotchkiss

Multidimensional, integrative profiling identifies BCL2L1 methylation as a predictor of MCL1 dependency in pediatric malignancies

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Pediatric high-grade gliomas (pHGGs) are the most aggressive brain tumors in children, necessitating innovative therapies to improve outcomes. Unlike adult gliomas, recent research reveals that childhood gliomas have distinct biological features, requiring specific treatment strategies. Here, we focused on deciphering unique genetic dependencies specific to childhood gliomas. Using a pooled CRISPR/Cas9 knockout screening approach on 65 pediatric and 10 adult high-grade glioma (HGG) cell lines, myeloid cell leukemia 1 (MCL1) emerged as a key antiapoptotic gene essential in pediatric but not adult gliomas. We demonstrated that MCL1 is targetable using current small molecule inhibitors, and its inhibition leads to potent anticancer activity across pediatric HGG cell lines irrespective of genotype. Employing predictive modeling approaches on a large set of childhood cancer cell lines with multiomics data features, we identified a potentially previously unreported cluster of CpG sites in the antiapoptotic BCL-xL/BCL2L1 gene, which predicted MCL1 inhibitor response. We extended these data across multiple pediatric tumor types, showing that BCL2L1 methylation is a broad predictor of MCL1 dependency in vitro and in vivo. Overall, our multidimensional, integrated genomic approach identified MCL1 as a promising therapeutic target in several BCL2L1-methylated pediatric cancers, offering a translational strategy to identify patients most likely to benefit from MCL1 inhibitor therapy.

Authors

Shazia Adjumain, Paul Daniel, Claire Xin Sun, Gabrielle Bradshaw, Nicole J. Chew, Vanessa Tsui, Hanbyeol Lee, Melissa Loi, Nataliya Zhukova, Dilru Habarakada, Abigail Yoel, Vijesh G. Vaghjiani, Shaye Game, Louise E. Ludlow, Naama Neeman, E. Alejandro Sweet-Cordero, David D. Eisenstat, Jason E. Cain, Ron Firestein

Clinical and immunological outcomes after randomized trial of baked milk oral immunotherapy for milk allergy

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BACKGROUND Cow’s milk (CM) allergy is the most common food allergy in young children. Treatment with oral immunotherapy (OIT) has shown efficacy, but high rates of adverse reactions. The aim of this study was to determine whether baked milk OIT (BMOIT) could reduce adverse reactions while still inducing desensitization, and to identify immunological correlates of successful BMOIT.METHODS This phase II, randomized trial evaluated the safety and efficacy of BMOIT in milk-allergic children 3–18 years old. After the initial placebo-controlled first year of treatment, placebo-treated participants crossed over to active BMOIT. Double-blind, placebo-controlled oral food challenges (OFCs) were conducted with BM after year 1 and to both BM and unheated milk (UM) after year 2. IgG and IgE antibodies were measured along with CM-specific (CM+) CD4+ memory T cell populations, profiled using flow cytometry and scRNA-Seq.RESULTS Twenty-one of 30 (70%) reached the primary endpoint of tolerating 4044 mg of BM protein at month 24, and 11 of 30 tolerated 2000 mg or more of UM protein. Dosing symptoms were common, but more than 98% were mild, with no severe reactions. Immunological changes associated with desensitization included increased CM IgG4, CM+ FOXP3+ cells, and Tregs and corresponding decreases in CM IgE, CM+ Th2A cells, and CD154+ cells. T cell and antibody measurements were combined to build a model that predicted UM OFC outcomes.CONCLUSION BMOIT was well tolerated and induced desensitization to BM and UM. This desensitization corresponded to redistribution within antigen-specific antibody and T cell compartments that provided insight into the mechanistic changes that occur with OIT treatment.TRIAL REGISTRATION ClinicalTrials.gov NCT03462030.FUNDING: Myra Reinhardt Family Foundation (grant number 128388), NIH/NIAID (U19AI135731, T32AI125179, S10OD025052)

Authors

Jennifer A. Dantzer, Sloan A. Lewis, Kevin J. Psoter, Aaron Sutherland, April Frazier, Eve Richardson, Synaida Maiche, Gregory Seumois, Bjoern Peters, Robert A. Wood

Randomised trial of same vs opposite arm co-administration of inactivated influenza and SARS-CoV-2 mRNA vaccines

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BACKGROUND. The immunogenicity of current influenza vaccines need improvement. Inactivated influenza and COVID-19 mRNA vaccines can be co-administered but randomized controlled trial data is lacking on whether the two vaccines are more immunogenic if given in the same or opposite arms. Murine studies suggest mRNA vaccines can adjuvant influenza vaccines when co-formulated and delivered together. METHODS. We randomly assigned 56 adults to receive the Afluria quadrivalent inactivated influenza and Moderna monovalent SARS-CoV-2 XBB.1.5 mRNA vaccines, either in opposite arms or both in the same arm at the same site. The primary endpoint was the difference in median combined serum haemagglutination inhibition titre to the H1, H3 and B-Vic vaccine influenza strains after vaccination. RESULTS. We found no significant difference in haemagglutination inhibition antibody levels between the groups (p = 0.30), with the same arm group having a 1.26-fold higher titre than the opposite arm group. There was no difference in analyses of antibodies to individual influenza strains, nor in nasal or saliva antibody levels. While both binding and neutralising antibody titres against SARS-CoV-2 were not significantly different between groups post-vaccination, there was a higher fold-change in BA.5 and ancestral strain neutralising antibodies in the opposite arm group. CONCLUSION. Influenza vaccination is equivalently immunogenic if given in same or opposite arms as the SARS-CoV-2 vaccine, but it may be preferable to administer the SARS-CoV-2 vaccine at a different site to influenza vaccines. TRIAL REGISTRATION. Australian New Zealand Clinical Trials Registry ACTRN12624000445572. FUNDING. Australian National Health and Medical Research Council and Medical Research Future Fund.

Authors

Wen Shi Lee, Kevin J. Selva, Jennifer Audsley, Helen E. Kent, Arnold Reynaldi, Timothy E. Schlub, Deborah Cromer, David S. Khoury, Heidi Peck, Malet Aban, Mai Ngoc Vu, Ming Z. M. Zheng, Amy W. Chung, Marios Koutsakos, Hyon-Xhi Tan, Adam K. Wheatley, Jennifer A. Juno, Steven Rockman, Miles P. Davenport, Ian Barr, Stephen J. Kent

A randomized, double-blind, placebo-controlled study of a GHSR blocker in people with alcohol use disorder

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BACKGROUND Studies have demonstrated the role of ghrelin in alcohol-related behaviors and consumption. Blockade of the growth hormone secretagogue receptor (GHSR), which is the ghrelin receptor, has been shown to decrease alcohol drinking and reward-related behaviors across several animal models. We previously conducted a human study testing a GHSR inverse agonist/competitive antagonist, PF-5190457, in individuals who are heavy drinkers and showed its safety when coadministered with alcohol. Here, we conducted a phase IIa experimental medicine study in patients with alcohol use disorder (AUD) to investigate the effects of PF-5190457 on alcohol- and food-related outcomes.METHODS Forty-two individuals with AUD (n = 29 completers) participated in a randomized, double-blind, placebo-controlled study where they received PF-5190457 100mg b.i.d. (or placebo) in 2 counterbalanced, within-subject stages. Participants completed an alcohol cue-reactivity (CR) experiment in a bar-like laboratory and a virtual food choice experiment in a cafeteria-like virtual reality (VR) environment. A subset of participants (n = 12) performed a CR task during a brain functional MRI (fMRI) experiment.RESULTS PF-5190457 did not reduce cue-elicited alcohol craving. PF-5190457 reduced virtual calories selected (P = 0.04) in the VR environment. PF-5190457 did not influence neural activation during CR task in the fMRI experiment.CONCLUSION This study provides human evidence of the role of GHSR blockade in behaviors related to food selection and highlights the need for future investigations into targeting the ghrelin system in AUD.TRIAL REGISTRATION ClinicalTrials.gov (accession no. NCT02707055).FUNDING NIDA and NIAAA ZIA-DA000635; National Center for Advancing Translational Sciences UH2/UH3-TR000963.

Authors

Monica L. Faulkner, Mehdi Farokhnia, Mary R. Lee, Lisa Farinelli, Brittney D. Browning, Kelly Abshire, Allison M. Daurio, Vikas Munjal, Sara L. Deschaine, Selim R. Boukabara, Christopher Fortney, Garrick Sherman, Melanie Schwandt, Fatemeh Akhlaghi, Reza Momenan, Thomas J. Ross, Susan Persky, Lorenzo Leggio

Inhibition of Bruton’s tyrosine kinase with PD-1 blockade modulates T cell activation in solid tumors

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BACKGROUND Inhibition of Bruton’s tyrosine kinase with ibrutinib blocks the function of myeloid-derived suppressor cells (MDSC). The combination of ibrutinib and nivolumab was tested in patients with metastatic solid tumors.METHODS Sixteen patients received ibrutinib 420 mg p.o. daily with nivolumab 240 mg i.v. on days 1 and 15 of a 28-day cycle. The effect of ibrutinib and nivolumab on MDSC, the immune profile, and cytokine levels were measured. Single-cell RNA-Seq and T cell receptor sequencing of immune cells was performed.RESULTS Common adverse events were fatigue and anorexia. Four patients had partial responses and 4 had stable disease at 3 months (average 6.5 months, range 3.5–14.6). Median overall survival (OS) was 10.8 months. Seven days of Bruton’s tyrosine kinase (BTK) inhibition significantly increased the proportion of monocytic-MDSC (M-MDSC) and significantly decreased chemokines associated with MDSC recruitment and accumulation (CCL2, CCL3, CCL4, CCL13). Single-cell RNA-Seq revealed ibrutinib-induced downregulation of genes associated with MDSC-suppressive function (TIMP1, CXCL8, VEGFA, HIF1A), reduced MDSC interactions with exhausted CD8+ T cells, and decreased TCR repertoire diversity. The addition of nivolumab significantly increased circulating NK and CD8+ T cells and increased CD8+ T cell proliferation. Exploratory analyses suggest that MDSC and T cell gene expression and TCR repertoire diversity were differentially affected by BTK inhibition according to patient response.CONCLUSION Ibrutinib and nivolumab were well tolerated and affected MDSC and T cell function in patients with solid metastatic tumors.TRIAL REGISTRATION ClinicalTrials.gov NCT03525925.FUNDING NIH; National Cancer Institute Cancer; National Center for Advancing Translational Sciences; Pelotonia.

Authors

Emily Schwarz, Brooke Benner, Robert Wesolowski, Dionisia Quiroga, Logan Good, Steven H. Sun, Himanshu Savardekar, Jianying Li, Kyeong Joo Jung, Megan C. Duggan, Gabriella Lapurga, Jami Shaffer, Luke Scarberry, Bhavana Konda, Claire Verschraegen, Kari Kendra, Manisha Shah, Robert Rupert, Paul Monk, Hiral A. Shah, Anne M. Noonan, Kristin Bixel, John Hays, Lai Wei, Xueliang Pan, Gregory Behbehani, Yang Hu, Olivier Elemento, Dongjun Chung, Gang Xin, Bradley W. Blaser, William E. Carson III

SLC6A19 inhibition facilitates urinary neutral amino acid excretion and lowers plasma phenylalanine

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BACKGROUND The toxic accumulation of phenylalanine (Phe) in the brain underlies the neurological presentation of phenylketonuria (PKU). Solute carrier family 6 member 19 (SLC6A19) is the major transporter responsible for the (re)absorption of Phe in the kidney and intestine. Here, we describe the characterization of the first small molecule SLC6A19 inhibitor to enter clinical development for the treatment of PKU.METHODS C57Bl/6J WT and Pahenu2 mice were dosed with an inhibitor of SLC6A19 to investigate the effects on urinary amino acids and plasma Phe. In a phase 1 study, healthy human volunteers were dosed with JNT-517, an investigational oral inhibitor of SLC6A19. The primary objective of the study was safety. Secondary objectives included pharmacokinetic and pharmacodynamic studies.RESULTS Inhibition of SLC6A19 increased the urinary excretion of Phe in a mouse model of PKU, thereby reducing plasma Phe levels. JNT-517, an investigational oral SLC6A19 inhibitor, was found to be safe and well tolerated and increased the urinary excretion of Phe in a phase 1 healthy volunteer study.CONCLUSIONS These data indicate that pharmacological inhibition of SLC6A19 presents a promising approach to lower toxic elevated levels of amino acids found in PKU and related amino acid metabolism disorders by facilitating their renal elimination.TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12622001222730.FUNDING The studies in this paper were funded by Jnana Therapeutics.

Authors

Heike J. Wobst, Andreu Viader, Giovanni Muncipinto, Ryan Hollibaugh, Daniel van Kalken, Christopher T. Burkhart, Susan M. Cantin, Rachel M. Bates, Yannik Regimbald-Dumas, Liam Gross, Mitchell T. Antalek, Joshua E. Zweig, Frank Wu, T. Justin Rettenmaier, Matthew T. Labenski, Nicholas Pullen, Heather S. Blanchette, Jaclyn L. Henderson, Haoling H. Weng, Toby A. Vaughn, Dean G. Brown, John P. Throup, Joel C. Barrish

Focusing HIV-1 Gag T-cell Responses to Highly Conserved Regions by DNA Vaccination in HVTN 119

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BACKGROUND. An HIV-1 DNA vaccine composed of seven highly conserved, structurally important elements (Conserved Elements, CE) of HIV p24Gag was tested in a phase I randomized, double-blind clinical trial (HVTN 119, NCT03181789) in people without HIV. A CE prime- CE+full-length p55Gag boost DNA vaccine was compared to p55Gag DNA vaccination only. METHODS. Two groups (n=25 each) received 4 DNA vaccinations [2xCE prime- 2xCE+p55Gag boost or 4x p55Gag] by intramuscular injection/electroporation, including IL-12 DNA adjuvant. The placebo group (n=6) received saline. Participants were followed for safety and tolerability. Immunogenicity was assessed for T cell and antibody responses. RESULTS. Both regimens were safe and generally well-tolerated. The p24CE vaccine was immunogenic (29% CD4+ and 4% CD8+ responders) and was significantly boosted by CE+p55Gag (64% CD4+, p=0.037; 42% CD8+, p=0.004). CE+p55Gag induced CD4+ responses to 5 of 7 CE, compared to only 2 CE by p55Gag DNA alone, with a higher reponse to CE5 in 30% of individuals (p=0.006). CE+p55Gag induced significantly higher mean CD4+ CE Tcell breadth (0.68 vs 0.22 CE; p=0.029) and a strong trend for increased CD4+ and CD8+ T-cell breadth (1.14 vs. 0.52 CE; p=0.051) compared to p55Gag alone. Both groups developed high p55Gag T-cell (91% each) and p24Gag antibody (91% vs. 80%) responses. p24CE vaccine-induced CD4+ CE T-cell responses correlated (p=0.007) with p24Gag antibody responses. CONCLUSION. The combination CE/CE+p55Gag DNA vaccine induced T-cell immune responses to conserved regions in p24Gag resulting in significant increases in breadth and epitope recognition throughout p55Gag. Vaccines able to focus immune responses by priming responses to highly conserved regions could be part of a comprehensive HIV vaccine strategy. TRIAL REGISTRATION. Clinical Trials.gov NCT03181789 Study URL: https://www.clinicaltrials.gov/search?term=NCT03181789 FUNDING. HIV vaccine trial network (HVTN), NIAID/NIH

Authors

Spyros A. Kalams, Barbara K. Felber, James I. Mullins, Hyman M. Scott, Mary A. Allen, Stephen C. De Rosa, Jack Heptinstall, Georgia D. Tomaras, Jiani Hu, Allan C. deCamp, Margherita Rosati, Jenifer Bear, Michael N. Pensiero, John Eldridge, Michael A. Egan, Drew Hannaman, M. Juliana McElrath, George N. Pavlakis