The adoptive cell transfer (ACT) of T cells targeting mutated neoantigens can cause objective responses in varieties of metastatic cancers, but the development of new T cell–based treatments relies on accurate animal models. To investigate the therapeutic effect of targeting a neoantigen with ACT, we used T cells from pmel-1 T cell receptor–transgenic mice, known to recognize a WT peptide, gp100, and a mutated version of the peptide that has higher avidity. We gene-engineered B16 cells to express the WT or mutated gp100 epitopes and found that pmel-1–specific T cells targeting a neoantigen tumor target augmented recognition as measured by IFN-γ production. Neoantigen expression by B16 also enhanced the capacity of pmel-1 T cells to trigger the complete and durable regression of large, established, vascularized tumor and required less lymphodepleting conditioning. Targeting neoantigen uncovered the possibility of using enforced expression of the IL-2Rα chain (CD25) in mutation-reactive CD8+ T cells to improve their antitumor functionality. These data reveal that targeting of “mutated-self” neoantigens may lead to improved efficacy and reduced toxicities of T cell–based cellular immunotherapies for patients with cancer.
Ken-ichi Hanada, Zhiya Yu, Gabrielle R. Chappell, Adam S. Park, Nicholas P. Restifo
Induction of a potent CD4 and CD8 T-cell response against tumor-specific and tumor-associated antigen is critical for eliminating tumor cells. Recent vaccination strategies have been hampered by an inefficacious and low amplitude immune response. Here we describe a self-adjuvanted chimeric protein vaccine platform to address these challenges, characterized by a multidomain construction incorporating (i) a cell penetrating peptide (CPP) allowing internalization of several multiantigenic Major Histocompatibility Complex (MHC)-restricted peptides within (ii) the multiantigenic domain (Mad) and (iii) a TLR2/4 agonist domain (TLRag). Functionality of the resulting chimeric protein is based on the combined effect of the above-mentioned three different domains for simultaneous activation of antigen presenting cells and antigen cross-presentation, leading to an efficacious multiantigenic and multiallelic cellular immune response. Helper and cytotoxic T-cell responses were observed against model-, neo- and self-antigens, and were highly potent in several murine tumor models. The safety and the immunogenicity of a human vaccine candidate designed for colorectal cancer treatment was demonstrated in a non-human primate model. This newly engineered therapeutic vaccine approach is promising for the treatment of poorly infiltrated tumors that do not respond to currently marketed immunotherapies.
Elodie Belnoue, Jean-François Mayol, Susanna Carboni, Wilma Di Berardino Besson, Eloise Dupuychaffray, Annika Nelde, Stefan Stevanovic, Marie-Laure Santiago-Raber, Paul R. Walker, Madiha Derouazi
Pathogen recognition receptor (PRR) agonists are currently being developed and tested as adjuvants in various formulations to optimize the immunogenicity and efficacy of vaccines. Using an original in vitro approach to prime naive precursors from unfractionated human peripheral blood mononuclear cells, we assessed the influence of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), a ligand for the stimulator of interferon genes (STING), on the induction of antigen-specific CD8+ T cells. We found that 2′3′-cGAMP and 3′3′-cGAMP were especially potent adjuvants in this system, driving the expansion and maturation of functionally replete antigen-specific CD8+ T cells via the induction of type I IFNs. The biological relevance of these findings was confirmed in vivo using two mouse models, in which 2′3′-cGAMP–adjuvanted vaccination elicited protective antitumor or antiviral CD8+ T cell responses. These results identify particular isoforms of cGAMP as effective adjuvants that may find utility in the development of novel immunotherapies and vaccines.
Alice Gutjahr, Laura Papagno, Francesco Nicoli, Tomohiro Kanuma, Nozomi Kuse, Mariela Pires Cabral-Piccin, Nicolas Rochereau, Emma Gostick, Thierry Lioux, Eric Perouzel, David A. Price, Masafumi Takiguchi, Bernard Verrier, Takuya Yamamoto, Stéphane Paul, Victor Appay
Antibodies and cytotoxic T cells represent 2 arms of host defense against pathogens. We hypothesized that vaccines that induce both high-magnitude CD8+ T cell responses and antibody responses might confer enhanced protection against HIV. To test this hypothesis, we immunized 3 groups of nonhuman primates: (a) Group 1, which includes sequential immunization regimen involving heterologous viral vectors (HVVs) comprising vesicular stomatitis virus, vaccinia virus, and adenovirus serotype 5–expressing SIVmac239 Gag; (b) Group 2, which includes immunization with a clade C HIV-1 envelope (Env) gp140 protein adjuvanted with nanoparticles containing a TLR7/8 agonist (3M-052); and (c) Group 3, which includes a combination of both regimens. Immunization with HVVs induced very high–magnitude Gag-specific CD8+ T cell responses in blood and tissue-resident CD8+ memory T cells in vaginal mucosa. Immunization with 3M-052 adjuvanted Env protein induced robust and persistent antibody responses and long-lasting innate responses. Despite similar antibody titers in Groups 2 and 3, there was enhanced protection in the younger animals in Group 3, against intravaginal infection with a heterologous SHIV strain. This protection correlated with the magnitude of the serum and vaginal Env-specific antibody titers on the day of challenge. Thus, vaccination strategies that induce both CD8+ T cell and antibody responses can confer enhanced protection against infection.
Caroline Petitdemange, Sudhir Pai Kasturi, Pamela A. Kozlowski, Rafiq Nabi, Clare F. Quarnstrom, Pradeep Babu Jagadeesh Reddy, Cynthia A. Derdeyn, Lori M. Spicer, Parin Patel, Traci Legere, Yevgeniy O. Kovalenkov, Celia C. Labranche, François Villinger, Mark Tomai, John Vasilakos, Barton Haynes, C. Yong Kang, James S. Gibbs, Jonathan W. Yewdell, Dan Barouch, Jens Wrammert, David Montefiori, Eric Hunter, Rama R. Amara, David Masopust, Bali Pulendran
BACKGROUND. Noroviruses are the leading cause of epidemic acute gastroenteritis and foodborne diarrheal disease in humans. However, there are no approved vaccines for noroviruses. Potential correlates of protection identified through human challenge studies include mucosal IgA, memory B cells, and serum-blocking antibody titers (BT50). METHODS. We conducted a single-site, randomized, double-blind, placebo-controlled clinical trial of an oral norovirus vaccine to determine safety and immunogenicity. This tablet vaccine is comprised of a nonreplicating adenovirus-based vector expressing the VP1 gene from the GI.1 norovirus strain and a double-stranded RNA adjuvant. Sixty-six adult subjects meeting inclusion/exclusion criteria were randomized 2:1 to receive a single vaccine dose or placebo, respectively. Immunogenicity was primarily assessed by serum BT50. Additional outcomes included serum ELISA titers, fecal and saliva antibody titers, memory and antibody-secreting cell (ASC) frequency, and B cell phenotyping. RESULTS. The vaccine was well-tolerated, with no dose-limiting toxicities. Adverse events were mild or moderate. The primary immunological endpoint (increase in BT50 titers) was met in the high-dose group (P = 0.0003), with 78% showing a ≥2-fold rise in titers after a single immunization. Vaccine recipients also developed mucosally primed VP1-specific circulating ASCs, IgA+ memory B cells expressing gut-homing receptor (α4β7), and fecal IgA, indicating substantial and local responses potentially relevant to prevent norovirus infection. CONCLUSION. This oral norovirus vaccine was well-tolerated and generated substantial immune responses, including systemic and mucosal antibodies as well as memory IgA/IgG. These results are a major step forward for the development of a safe and immunogenic oral norovirus vaccine. TRIAL REGISTRATION. ClinicalTrials.gov NCT02868073. FUNDING. Vaxart.
Leesun Kim, David Liebowitz, Karen Lin, Kassandra Kasparek, Marcela F. Pasetti, Shaily J. Garg, Keith Gottlieb, George Trager, Sean N. Tucker
Transmission-blocking vaccines (TBVs) are considered an integral element of malaria eradication efforts. Despite promising evaluations of Plasmodium falciparum Pfs25-based TBVs in mice, clinical trials have failed to induce robust and long-lived Ab titers, in part due to the poorly immunogenic nature of Pfs25. Using nonhuman primates, we demonstrate that multiple aspects of Pfs25 immunity were enhanced by antigen encapsulation in poly(lactic-co-glycolic acid)–based [(PLGA)-based] synthetic vaccine particles (SVP[Pfs25]) and potent TLR-based adjuvants. SVP[Pfs25] increased Ab titers, Pfs25-specific plasmablasts, circulating memory B cells, and plasma cells in the bone marrow when benchmarked against the clinically tested multimeric form Pfs25-EPA given with GLA-LSQ. SVP[Pfs25] also induced the first reported Pfs25-specific circulating Th1 and Tfh cells to our knowledge. Multivariate correlative analysis indicated several mechanisms for the improved Ab responses. While Pfs25-specific B cells were responsible for increasing Ab titers, T cell responses stimulated increased Ab avidity. The innate immune activation differentially stimulated by the adjuvants revealed a strong correlation between type I IFN polarization, induced by R848 and CpG, and increased Ab half-life and longevity. Collectively, the data identify ways to improve vaccine-induced immunity to poorly immunogenic proteins, both by the choice of antigen and adjuvant formulation, and highlight underlying immunological mechanisms.
Elizabeth A. Thompson, Sebastian Ols, Kazutoyo Miura, Kelly Rausch, David L. Narum, Mats Spångberg, Michal Juraska, Ulrike Wille-Reece, Amy Weiner, Randall F. Howard, Carole A. Long, Patrick E. Duffy, Lloyd Johnston, Conlin P. O’Neil, Karin Loré
BACKGROUND. Heat shock protein peptide complex-96 (HSPPC-96) triggers adaptive and innate antitumor immune responses. The safety and efficacy of HSPPC-96 vaccination was examined in patients with newly diagnosed glioblastoma multiforme (GBM). METHODS. In this open-label, single-arm, phase I study, adult patients were vaccinated with HSPPC-96 in combination with the standard treatment for newly diagnosed GBM after surgical resection. Primary endpoints were frequency of adverse events and progression-free survival (PFS) at 6 months. Secondary endpoints included overall survival (OS), PFS, and tumor-specific immune response (TSIR). RESULTS. A total of 20 patients with newly diagnosed GBM were enrolled from September 2013 to February 2015. No grade 3 or 4 vaccine-related adverse events were noted. After a median follow-up of 42.3 months, PFS was 89.5% (95% CI, 66.9%–98.7%) at 6 months, median PFS was 11.0 months (95% CI, 8.2–13.8), and median OS was 31.4 months (95% CI, 14.9–47.9). TSIR was significantly increased by 2.3-fold (95% CI, 1.7–3.2) after vaccination. Median OS for patients with high TSIR after vaccination was >40.5 months (95% CI, incalculable) as compared with 14.6 months (95% CI, 7.0–22.2) for patients with low TSIR after vaccination (hazard ratio, 0.25; 95% CI, 0.071–0.90; P = 0.034). A multivariate Cox regression model revealed TSIR after vaccination as a primary independent predicator for survival. CONCLUSION. The HSPPC-96 vaccination, combined with the standard therapy, is a safe and effective strategy for treatment of newly diagnosed GBM patients. TSIR after vaccination would be a good indicator predicting the vaccine efficacy. TRIAL REGISTRATION. ClinicalTrials.gov NCT02122822. FUNDING. National Key Technology Research and Development Program of the Ministry of Science and Technology of China (2014BAI04B01, 2014BAI04B02), Beijing Natural Science Foundation (7164253), Beijing Talents Fund (2014000021469G257), and Shenzhen Science and Technology Innovation Committee (JSGG20170413151359491).
Nan Ji, Yang Zhang, Yunpeng Liu, Jian Xie, Yi Wang, Shuyu Hao, Zhixian Gao
Low-grade gliomas (LGGs) are the most common brain tumor affecting children. We recently reported an early phase clinical trial of a peptide-based vaccine, which elicited consistent antigen-specific T cell responses in pediatric LGG patients. Additionally, we observed radiologic responses of stable disease (SD), partial response (PR), and near-complete/complete response (CR) following therapy. To identify biomarkers of clinical response in peripheral blood, we performed RNA sequencing on PBMC samples collected at multiple time points. Patients who showed CR demonstrated elevated levels of T cell activation markers, accompanied by a cytotoxic T cell response shortly after treatment initiation. At week 34, patients with CR demonstrated both IFN signaling and Poly-IC:LC adjuvant response patterns. Patients with PR demonstrated a unique, late monocyte response signature. Interestingly, HLA-V expression, before or during therapy, and an early monocytic hematopoietic response were strongly associated with SD. Finally, low IDO1 and PD-L1 expression before treatment and early elevated levels of T cell activation markers were associated with prolonged progression-free survival. Overall, our data support the presence of unique peripheral immune patterns in LGG patients associated with different radiographic responses to our peptide vaccine immunotherapy. Future clinical trials, including our ongoing phase II LGG vaccine immunotherapy, should monitor these response patterns.
Sören Müller, Sameer Agnihotri, Karsen E. Shoger, Max I. Myers, Nicholas Smith, Srilakshmi Chaparala, Clarence R. Villanueva, Ansuman Chattopadhyay, Adrian V. Lee, Lisa H. Butterfield, Aaron Diaz, Hideho Okada, Ian F. Pollack, Gary Kohanbash
Major advances in donor identification, antigen probe design, and experimental methods to clone pathogen-specific antibodies have led to an exponential growth in the number of newly characterized broadly neutralizing antibodies (bnAbs) that recognize the HIV-1 envelope glycoprotein. Characterization of these bnAbs has defined new epitopes and novel modes of recognition that can result in potent neutralization of HIV-1. However, the translation of envelope recognition profiles in biophysical assays into an understanding of in vivo activity has lagged behind, and identification of subjects and mAbs with potent antiviral activity has remained reliant on empirical evaluation of neutralization potency and breadth. To begin to address this discrepancy between recombinant protein recognition and virus neutralization, we studied the fine epitope specificity of a panel of CD4-binding site (CD4bs) antibodies to define the molecular recognition features of functionally potent humoral responses targeting the HIV-1 envelope site bound by CD4. Whereas previous studies have used neutralization data and machine-learning methods to provide epitope maps, here, this approach was reversed, demonstrating that simple binding assays of fine epitope specificity can prospectively identify broadly neutralizing CD4bs–specific mAbs. Building on this result, we show that epitope mapping and prediction of neutralization breadth can also be accomplished in the assessment of polyclonal serum responses. Thus, this study identifies a set of CD4bs bnAb signature amino acid residues and demonstrates that sensitivity to mutations at signature positions is sufficient to predict neutralization breadth of polyclonal sera with a high degree of accuracy across cohorts and across clades.
Hao D. Cheng, Sebastian K. Grimm, Morgan S.A. Gilman, Luc Christian Gwom, Devin Sok, Christopher Sundling, Gina Donofrio, Gunilla B. Karlsson Hedestam, Mattia Bonsignori, Barton F. Haynes, Timothy P. Lahey, Isaac Maro, C. Fordham von Reyn, Miroslaw K. Gorny, Susan Zolla-Pazner, Bruce D. Walker, Galit Alter, Dennis R. Burton, Merlin L. Robb, Shelly J. Krebs, Michael S. Seaman, Chris Bailey-Kellogg, Margaret E. Ackerman
Declining levels of maternal antibodies were shown to sensitize infants born to dengue-immune mothers to severe disease during primary infection, through the process of antibody-dependent enhancement of infection (ADE). With the recent approval for human use of Sanofi-Pasteur’s chimeric dengue vaccine CYD-TDV and several vaccine candidates in clinical development, the scenario of infants born to vaccinated mothers has become a reality. This raises 2 questions: will declining levels of maternal vaccine-induced antibodies cause ADE; and, will maternal antibodies interfere with vaccination efficacy in the infant? To address these questions, the above scenario was modeled in mice. Type I IFN–deficient female mice were immunized with live attenuated DENV2 PDK53, the core component of the tetravalent DENVax candidate currently under clinical development. Pups born to PDK53-immunized dams acquired maternal antibodies that strongly neutralized parental strain 16681, but not the heterologous DENV2 strain D2Y98P-PP1, and instead caused ADE during primary infection with this strain. Furthermore, pups failed to seroconvert after PDK53 vaccination, owing to maternal antibody interference. However, a cross-protective multifunctional CD8+ T cell response did develop. Thus, our work advocates for the development of dengue vaccine candidates that induce protective CD8+ T cells despite the presence of enhancing, interfering maternal antibodies.
Jian Hang Lam, Yen Leong Chua, Pei Xuan Lee, Julia María Martínez Gómez, Eng Eong Ooi, Sylvie Alonso
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