Gene Therapy to Combat HIV
Presenter: Hans-Peter Kiem, MD, PhD, Director, Stem Cell and Gene Therapy Program Clinical Research Division, Fred Hutchinson Cancer Research Center, Professor, University of Washington School of Medicine, Seattle, WA
A summary of Setting the Stage for the Use of Cell and Gene Therapy to Enhance Control or Eradication of HIV from the session HIV Cure and Gene Therapy Forum, presented July 19, 2021, the 11th International AIDS Society (IAS) Conference on HIV Science.
Gene therapies currently under investigation may one day enhance the control or eradication of HIV.
Chimeric antigen receptor (CAR) T-cells have been successfully used in cancer therapies, especially in patients with lymphoid malignancies, directed against the surface antigen of CD19, CD20, or B-cell maturation antigen. These CAR T cell-therapies in many cases have replaced allogeneic transplants.
“We hypothesized that CAR T-cells could also be used in the HIV setting. We could have CAR T-cells directed against the HIV envelope, for example, and use the patient’s own cells in the autologous setting to modify the patient’s cells with CAR constructs,” said Hans-Peter Kiem, MD, PhD, Director, Stem Cell and Gene Therapy Program Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
“We can introduce gene editing and use it to modify hematopoietic stem cells. The modification will get passed down to all the blood lineages, making them all resistant to HIV. Then we can knock in a CAR construct to generate CAR T-cells and possibly CAR macrophages, as well as in a bNAb (broadly neutralizing antibody) so B cells will produce these proteins in the long term. We also can modify or target T cells or B cells directly,” said Kiem.
Kiem and colleagues recently reported that CAR T-cells can be generated against HIV using modified peripheral blood T-cells. They used an antigen-boosting technology to improve CAR T-cell manufacturing and found robust expansion of HIV T-cells in a non-human primate (NHP) model.
Using the NHP model of HIV in another study, Fred Hutchinson and University of California, Los Angeles researchers found that a simple CAR construct recognized the gp120 protein on the cell surface, allowing “the stem cells to provide multilineage engraftment in these animals long-term. These cells trafficked to HIV reservoirs, like the lymphoid germinal centers, and also the central nervous system (CNS),” said Kiem.
To overcome some limitations of T-cell-based CAR T-cells in HIV, they noted that “stem-cell-based CAR T- cells would allow for the long-term persistence in the high, low, or even no antigen setting. Infected cells may remain latent for months or years, and stem cell CAR T-cells correspondingly wax and wane in response to viral antigen loads. Limited trafficking to tissues where HIV-1 persists may be a problem with peripheral blood T-cell-derived CARs. Stem cell CARs may be more efficient in trafficking to B-cell follicles and other tissues, like the gastrointestinal tract or CNS,” he said.
Ex-vivo gene therapy approaches still require expensive high-tech facilities and “would not be available to the millions of people living with HIV,” said Kiem. “We could do it all in one closed system, but this still requires a transplant center, especially if high doses of chemotherapy are required for the engraftment of genetically modified cells.”
In speaking about in vivo therapies, Kiem stated that “we would mobilize stem cells into the blood and with a single injection target them into the patient directly. We could manufacture this offsite, whether it’s a nanoparticle or biovector, and then ship it around the world and then it would be injected into the patient, thereby providing a portable gene therapy system.”
In vivo delivery approaches now under investigation include polymer-based and gold nanoparticles and lipid nanoparticles, including for vaccination purposes.
What are the requirements for in vivo gene therapy? “We want a safe approach that is portable, achieves viral remission, is durable, affordable, and repeatable,” said Kiem.
Disclosure
Hans-Peter Kiem, MD, PhD, reported nothing to disclose.
References
Rust BJ, Kean LS, Colonna L, et al. Robust expansion of HIV CAR T cells following antigen boosting in ART-suppressed nonhuman primates. Blood 2020; 136(15):1722–1734. doi: 0.1182/blood.2020006372.
Zhen A, Peterson CW, Carrillo MA, et al. Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS. PLOS Pathogens 2017; 13(12):e1006753. doi: 10.1371/journal.ppat.1006753