UM1AI191272

Individualized HIV curative combination strategy against persistent HIV on ART - Summary

We have demonstrated multiple lines of evidence supporting the role for autologous neutralizing antibodies (ANABs) to restrict virus rebound.

The positive relationship between ANAB suppression of virus reactivation ex vivo and time to rebound in vivo indicates that ANABs are a strong host determinant in the suppression of the HIV viral reservoir.

This offers a unique opportunity to develop an individualized HIV cure strategy targeting the ANAB-resistant component of the HIV reservoir that is not controlled by the host upon reactivation.

Taking advantage of the full complement of immune responses (i.e., a combination of innate, humoral and cell-mediated components), this proposal seeks to develop an individually tailored strategy that will bring together A) neutralizing antibody responses enhanced via mRNA-lipid nanoparticle (LNP) technology, B) ANAB-resistant HIV Env HLA-E restricted adaptive NK cells or creation of multi-specific molecules targeting the HIV loaded HLA-E MHC complex, and C) engineered cell-mediated effector strategies, consisting of multivalent CAR T cells and CD64-transduced NK cells with a membrane-bound combinations of broadly neutralizing antibodies optimized against the ANAB-resistant reservoir of each participant.

Our preliminary data indicates that each of the strategies proposed has potential for antiviral control, supporting their inclusion in the combined approach proposed.

Our central hypothesis is that characterization of the ANAB-resistant HIV reservoir will permit development of a targeted, personalized combination strategy of antiviral innate, humoral and cell-mediated responses, which together will elicit sustained viral control and/or viral eradication.

To test this hypothesis, we will first conduct comprehensive reservoir screens in persons with HIV suppressed on ART after early or late ART initiation (to evaluate strategies against distinct levels of reservoir diversity) to identify sequences of ANAB-resistant reservoir viruses which will be used to generate individual tailored ANABs (induced by mRNA-LNP-based vaccination) and, concurrently, to identify the best combination of existing broadly neutralizing antibodies (bNAbs) that can achieve virus control.

Second, we will build personalized cell-mediated responses to clear infected cells by (i) HLA-E responsive Env peptides for adaptive NK cell generation, (ii) phage display targeting for bi/tri-specific HLA-E-Env peptide complex engagers, and (iii) individually defined bNAb combinations loaded onto CD64-NK or expressed as tri-bNAb constructs on CAR T cells.

To facilitate future clinical deployment of this combined immune strategy, we will develop personalized virus reactivation strategies, wherein individual’s CD4+ cells bearing integrated HIV will be characterized to design personalized LRA approaches optimized to maximize HIV reactivation.

Together with significant institutional and industry commitment, our proposal brings together collaborative groups from Accelivir, Merck, Acuitas Therapeutics, BioNTech, Bluewhale Bio, CytoImmune Therapeutics, George Washington Univ., Univ. of Nebraska, Ragon Institute, Massachusetts Institute of Technology, Duke Univ., Philadelphia Fight Johns Hopkins Univ., Univ. of Pennsylvania, and Wistar Institute.

The Wistar Institute Of Anatomy And Biology

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Pennsylvania United States

State-Wide

Tailoring HIV Curative Strategies to the Participant (UM1 Clinical Trial Not Allowed) (RFA-AI-24-011)