The Research Question
CAR T cells against HIV were among the earliest CAR T cells developed. However, the greatest strides in the clinic have been made by deploying these cells to recognize and target certain cancers—the FDA approved two CAR T cell therapies against cancer in 2017.
A better strategy may be to create a type of CAR T cell that, like a skeleton key, can target multiple strains of HIV.CAR T cells are engineered to package the killing capacity of killer T cells together with the targeting ability of an antibody into a single T cell. Thus, a CAR T cell intervention can be designed to target one type of cancer, or rather, a specific protein associated with that cancer. CAR T cell therapy has been a breakthrough, saving the lives of patients with certain types of lymphoma or leukemia.
However, HIV constantly mutates, making it difficult to identify an unchanging protein that can always be targeted by a CAR T cell. A better strategy may be to create a type of CAR T cell that, like a skeleton key, can target multiple strains of HIV without the need to manufacture as many different CAR T cells as there are strains of HIV.
Findings
amfAR-funded researchers recently published a paper describing such a product. The first step in creating this new CAR T cell was to modify broadly neutralizing antibodies that naturally target a variety of HIV strains, using the protein MicA. These modified antibodies are called micAbodies.
The authors concluded that these emerging technologies “create a promising killing platform for attacking the latent HIV reservoir.”The second step was to engineer killer T cells to recognize and bind to the MicA region of the micAbodies. These engineered CAR T cells bind micAbodies, which in turn bind to cells producing HIV. When a CAR T cell that is bound to a micAbody detects that the micAbody is in turn bound to an infected cell, the CAR T cell kills the infected cell.
Using this strategy, researchers were able to use what they have termed convertibleCAR-T cells with a combination of micAbodies to kill HIV-infected—but not uninfected—T cells. Within 48 hours, these convertibleCAR-T cells were able to reduce by half the reservoir of inducible, latently infected cells obtained from the blood and tissues of HIV-infected individuals on antiretroviral treatment.
Researchers are currently conducting mouse studies to test these convertibleCAR-T cells in vivo. Promising results would lead to further evaluation in monkeys and humans.
Impact
Unlike CAR T cells that are designed to kill only one form of a target cell, convertibleCAR-T cells are limited only by the variety of micAbodies present. Thus, a cocktail of micAbodies could target most of the HIV strains in circulation today. The authors concluded that these emerging technologies “create a promising killing platform for attacking the latent HIV reservoir.”
amfAR’s Role
Researchers involved with this study are affiliated with the amfAR Institute for HIV Cure Research.
Original Article
https://www.ncbi.nlm.nih.gov/pubmed/31668804