Luis J. Montaner, D.V.M., D.Phil.

In 2021, the BEAT-HIV Collaboratory received a second, five-year, $29.15 million Martin Delaney Collaboratory (MDC) award and was joined by a third principal investigator Robert  F. Siliciano, M.D., Ph.D., from Johns Hopkins University in addition to co-principal investigators Luis J. Montaner, D.V.M., D.Phil., from Wistar, and James L. Riley, Ph.D., from the University of Pennsylvania. The new award is one of 10 grants funded in 2021 by the National Institutes of Health’s (NIH) “Martin Delaney Collaboratories to Cure HIV” initiative to a highly-select group of U.S.-led teams charged with advancing global efforts to develop a cure for HIV. Building on the success of the initial award made in 2016, when the NIH granted nearly $23 million to the BEAT-HIV Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy. While the initial cycle from 2016-2021 funded the BEAT2 clinical trial, the most recent cycle of funding focuses more on basic science and did not include clinical trial support.

The BEAT-HIV Delaney Collaboratory is a partnership of more than 85 leading HIV investigators, from academia to industry partners working with community-based organization Philadelphia FIGHT, to test combinations of several novel immunotherapies under new preclinical research. The new cycle of BEAT-HIV funding established three research goals, based on goals outlined in the NIH program announcement:

• Understand the basic mechanisms underlying persistence of the viral reservoir during ART, what cell populations contribute to rebound after treatment interruption, and the role played by host-related factors.
  
  
• Develop strategies to achieve durable suppression of HIV replication in the absence of ART. Capitalizing on advances in clinical research on bNAbs, BEAT-HIV researchers will test synthetic DNA technology to better deliver the genetic blueprint for the body to make different specific bNAbs simultaneously. An additional approach will be to boost natural killer and T cell responses to achieve long-term viral suppression. Eventually, the two strategies will be combined to maximize long-term control potential.
  
  
• Develop new approaches to eradicate the HIV reservoir. Strategies to be tested include novel drugs able to reactivate latent HIV hiding in the immune cells, combined with CAR-T cell approaches designed to change a person’s killer T cells to make them able to find infected cells more efficiently. In addition, researchers will apply a technology called mRNA-LNP to make cells resistant to HIV. The ultimate goal is to identify which approaches have the best potential and test them in combination to achieve complete HIV eradication.

BEAT-HIV2 CLINICAL STUDIES – COMPLETE

We completed enrollment in each HIV cure-directed clinical trial funded under the BEAT-HIV umbrella from 2016-2021.

The first study was to determine if treatment with pegylated interferon alpha 2b (peg-IFN-α2b) together with neutralizing antibodies 3BNC117+10-1074 will result in a reduction of viral rebound and reduction in the amount of latent HIV DNA in peripheral blood cells and tissues of individuals with chronic HIV infection upon an antiretroviral treatment (ART) interruption. By measuring the changes in viral rebound after ART interruption as a surrogate measure of the latent reservoir and immune control, the study will establish if this combined immunotherapy strategy should be considered as a component of future viral eradication strategies. Visit ClinicalTrials.gov under NCT03588715 for more information. Visit ClinicalTrials.gov under NCT03588715 for more information. Data analysis is underway.

The second study tested a clinical strategy that combined two gene therapy vectors to genetically modify T cells purified from study participants using the chimeric antigen receptor (CAR) technology to make these cells highly specific in recognizing HIV-infected cells. In addition, these T cells will be made HIV-resistant by using Zinc-finger Nucleases (ZFNs) that target CCR5, an HIV entry molecule. As a result of these genetic modifications, immune cells will be rendered specific in their killing capacity while also resistant against HIV infection, which is expected to enhance their intrinsic ability to clear HIV-infected cells and result in durable viral suppression after suspension of the antiretroviral therapy. To learn more about this clinical trial, visit ClinicalTrials.gov (NCT03617198). Data analysis is underway.

HOME-BASED VIRAL LOAD TESTING DEVICE – ENROLLMENT COMPLETE

BEAT-HIV investigators partnered with Merck, Inc. and Tasso, Inc. to assess the reliability and acceptability of a home-based viral load testing device. The micro-blood collection device was previously tested concurrently with participants enrolled in each of the two BEAT-HIV clinical trials described above.

HIV cure-directed clinical trials often include an analytic treatment interruption (ATI, learn more about that here). ATIs require frequent clinic visits to monitor participants’ viral load to keep it within study safety guidelines. The COVID epidemic changed the research landscape, including a stated desire among study participants and community advocates to reduce the number of study visits (and potential exposure to COVID-19 during transit and at the clinic).

The device being tested could potentially reduce the number of required clinic visits for blood collection, but only if the home-based viral load device test works as well as standard lab-based viral load testing that can now only be done at the clinic. Just as important is to determine how people living with HIV feel about the device and the process for returning it to the lab by mail or courier, how comfortable they are with using the home-based device, and if they have any other concerns.

The home-based viral load testing device is currently being offered by invitation to participants resuming antiretroviral therapy. At this time, the home-based viral load testing device is available within an experimental framework to determine if: 1) the device is acceptable to participants and 2) if the device provides results that are comparable to those available with traditional clinic- or lab-based viral load testing.

The Montaner lab was awarded a five-year, $17 million research award in 2025 to launch the iCure Consortium and develop individualized ‘cure regimens’ for HIV. The Wistar-led iCure Consortium’s objective is to advance strategies to cure HIV through tailored, personalized medicine.

“Today 38 million people still live with HIV worldwide, and 1.3 million contract the virus each year,” said Luis J. Montaner, D.V.M., D.Phil., iCure principal investigator, executive vice president of The Wistar Institute and director of Wistar’s HIV Cure and Viral Diseases Center. “For the first time, this grant brings our best team together to work toward a cure tailored to each participant, pairing the latest neutralizing antibody and cell-therapy breakthroughs against the unique, person-specific features of HIV.”

iCure will develop a therapy strategy to create individually-tailored therapies designed to wipe out the persistent viral reservoir that remains after antiretroviral therapy, to deliver durable, drug-free remission. The project combines six advanced tactics—neutralizing antibodies, mRNA therapy, viral binders, engineered CAR-T and “Natural Killer” (NK) cells, and precision latency “wake-up” drugs—all designed against each patient’s unique virus.

iCure extend the research groundwork laid by the BEAT-HIV Martin Delaney Collaboratory (beat-hiv.org), a Philadelphia-based consortium of more than 95 leading HIV researchers co-led by Dr. Montaner.

Montaner called the NIH grant a ‘once in a lifetime opportunity’ that reflects Wistar’s track record as a scientific leader in the effort to develop an HIV cure, as well as its grassroots support and collaboration with the HIV community.

Other institutions participating in this study include Johns Hopkins Medicine—home to iCure co-principal investigator Robert Siliciano, M.D., Ph.D.—University of Pennsylvania, Philadelphia FIGHT, Ragon Institute at Harvard University, George Washington University, Duke University, and Massachusetts Institute of Technology. The iCure program is funded by the National Institute of Allergy and Infectious Diseases, part of NIH, under award number UM1AI191272.

Myeloid cells are critical components of the tumor microenvironment. Under physiological conditions these cells are comprised of mature terminally differentiated cells: polymorphonuclear neutrophils (PMN) and other granulocytes; macrophages (MΦ); and dendritic cells (DCs). In cancer, the myeloid compartment is dramatically affected, which is now considered one of the major immunological hallmarks of cancer. Tumor-bearing (TB) hosts accumulate immunosuppressive MΦ, DCs that are ineffective in inducing potent immune responses. The prominent change in the myeloid compartment in cancer is the expansion of pathologically activated immature myeloid cells with a potent ability to suppress immune responses — myeloid-derived suppressor cells (MDSC). In TB mice, the total population of MDSC consists of three groups of cells: pathologically activated neutrophils (PMN-MDSC) are the most abundant (>75%); pathologically activated monocytes (M-MDSC) are less abundant (<20%); and early myeloid precursors represent a small (<5%) population. The current view considers changes in myeloid cells separately, with different mechanisms applied to the different cell types. The gap in our knowledge is how these different myeloid cells can interact with each other in TB hosts. We are investigating the bridge between different populations of myeloid cells in cancer and how they orchestrate their abnormal function. The ultimate goal of this project is not only to better understand the mechanism regulating myeloid cell function in cancer, but to develop novel approaches for regulation of immune responses in cancer.

According to National Cancer Institute (NCI) statistics, ovarian cancer represents 1% of all cancers, and more than 19,000 women are diagnosed every year in the U.S. An estimated one woman in 87 will develop ovarian cancer during her lifetime. Although many therapeutic approaches have been tested, including surgery, radiation, chemotherapy, and immunotherapy, ovarian cancer remains extremely difficult to treat, and novel therapeutic approaches are needed. This project, funded in part by the Department of Defense, is based on therapeutic strategies that can modulate myeloid cell apoptosis resulting in an increase of anti-tumor immune responses.

Absent direct clinical trials in humans, animal models of HIV infection are the best platform to explore novel pre-clinical anti-HIV strategies. Animal models for HIV infection include nonhuman primates and humanized mice. Humanized mice have emerged as a model able to be used for high-volume screening, yet the suboptimal immune differentiation that occurs has raised concern on the ability of this model to fully reflect all aspects of an immune response otherwise present in humans. The humanized mouse system has been developed to model HIV infection in humans, response to antiretroviral therapy (ART) and novel cure interventions, as well as study cancer immunotherapy in patient-derived xenograft models. A new WistarHu mice platform has been developed to support cancer immunotherapy and Wistar-based discovery of strategies against HIV based on assessing changes in viral measures on ART or effects on viral load rebound after ART interruption (Analytical Therapy Interruption, ATI). In support of this new platform, we have established ART formulations, HIV infection, HIV suppression, and characterized changes on immune reconstitution, persistent HIV measures, microbial translocation after ART and during an ATI. This platform is currently applied toward discovery and collaborative work.

With long-standing commitment from Philadelphia FIGHT and the University of Pennsylvania along with the Robert I. Jacobs Fund of The Philadelphia Foundation, the HIV-1 Patient Partnership Program was established to provide clinical material for basic research and to sponsor the Jonathan Lax Memorial Lecture (also supported by Ken Nimblett in memory of his husband, Rusty Miller, and The Summerhill Trust, established by Martha Stengel Miller). Research with clinical material obtained from this program is focused on mechanisms of AIDS immunopathology. This collaborative link between our research team and over 6000 HIV-1 patients in the Philadelphia region led to the largest HIV Cure clinical trial to date — the BEAT-HIV Study from 2014-2018.

The HIV-1 patient-partnership program involving participants in research is based at Philadelphia FIGHT (a community-based HIV-1 primary care provider) and Prevention Point Philadelphia. Our partnership with each community-based organization strives to develop trusted relationships and maintain meaningful, bi-directional lines of communication between investigators and communities most affected by HIV and substance use disorder. The primary objective of our community engagement strategy is to ensure communities have a clear understanding of a) the research being implemented, whether HIV-cure directed or other HIV, COVID, or monkeypox (MPOX) research, b) the stage of the research (including setting realistic expectations around HIV cure science), and c) how interested individuals can participate in and support our research agenda.

Social Science was added to our HIV cure research agenda to enhance both our preclinical and community engagement efforts. The Social Sciences Initiative assesses the acceptability of HIV cure interventions under development and conducts empirical ethics research related to HIV cure. Working in close collaboration, BEAT-HIV investigators and community stakeholders have developed a robust agenda of educational activities, community-based projects, and basic/clinical research designed to ensure comprehensive understanding and to provide guidance on the ethical conduct of HIV cure-directed research.

Above all, the Montaner laboratory makes its research accountable to our study participants and other stakeholders through community advisory board (CAB) review and community representation on Data Safety Monitoring Boards for clinical trials when active. In addition, we provide community-focused research presentations at Philadelphia’s AIDS Education Month, the annual Lax Lecture, and other community events, so that community members and other interested individuals are informed about the outcomes of patient-supported research.

The Jonathan Lax Lecture honors the memory of Jonathan Lax, a businessman, inventor, teacher, and one of the best-known AIDS activists in Philadelphia’s community-based clinical research network, where he volunteered with many groups to try and speed the drug approval process. He left funds to start a clinic — today called the Jonathan Lax Center — that is now the largest provider of AIDS care in Philadelphia, independent of a patient’s ability to pay. The Lax Lecture is a public lecture held each year at The Wistar Institute, where leading international HIV scientists interact with local researchers, clinicians, and patient advocates. Previous speakers include Gates Foundation HIV Frontiers and Biotechnology Accelerator head Mike McCune, Partners in Health founder and Harvard professor Paul Farmer, Project Inform founder Martin Delaney, and 2008 Nobel Laureate Françoise Barré-Sinoussi. In 2021, the Lax Lecture celebrated its 25th year by honoring Anthony Fauci for his dedication to serving people living with HIV – the first person to receive this honor twice. The 2024 honoree is Nobel Laureate in Physiology or Medicine, Dr. Drew Weissman.