Combining CAR T Cell Strategies to Achieve an HIV Cure
amfAR researchers re-engage with anti-HIV CAR T cell therapies by exploring new ways to enhance their activity
By Jeffrey Laurence, M.D.
CAR T cell therapy has become a critical part of the arsenal against many blood-associated cancers such as leukemia and multiple myeloma. After T cells are collected from a patient, they are genetically engineered to produce chimeric antigen receptors (CARs), which can home in on specific proteins, or antigens, on cancer cells. After being grown to produce millions and reinfused into the patient, the CAR T cells zero in on cancer cells with the target antigen on their surface.
Initial trials to apply the same technology to control or eradicate HIV have been disappointing. However, subsequent advances in CAR design have renewed interest in this strategy as part of an HIV cure. amfAR recently funded several studies involving engineering of CAR T cells to render them resistant to HIV infection, and to refine the viral targets with which they interact.
But another key obstacle to effective anti-HIV CAR therapy is the limited persistence of such engineered cells in patients. Unlike the situation in blood cancers, in which a high tumor burden can activate and ensure persistence of CAR T cells, people living with HIV (PLWH) have low levels of HIV on their infected cell surfaces, and HIV reservoir cells have none.
In their paper, amfAR grantee Dr. Martin Tolstrup and colleagues from Aarhus University, Denmark, review methods used in their laboratories, and those of others, to enhance the expansion and persistence of anti-HIV CAR T cells and also discuss novel strategies. These processes include genetic modification of CAR and the use of different starting materials—e.g., naïve and stem cell memory T cells, rather than the unselected bulk populations of T cells typical of CAR cancer treatments.
Reduction of the size of the HIV latent reservoir by “lymphodepletion,” using standard anti-cancer medications; inducing latently infected cells to produce virus through the use of latency reversing agents; and HIV vaccination protocols are other promising adjuncts to CAR treatments.
The authors conclude that such “successful CAR T cell trials in HIV will likely require combinations of the described approaches to ensure persistence of the CAR T cells and ultimately achieve a cure for HIV.”
amfAR was a funder of this research.
Dr. Laurence is amfAR’s senior scientific consultant.