Abstract: Science has made great progress in the fight against HIV and AIDS over the last decade. And a new platform called ConvertibleCAR has shown great potential.
AIDS has always been the focus of research in medical circles in various countries, because it is a disease that is relatively difficult to cure at the current medical level, and it also damages the human immune system greatly, and thus is easy to cause complications and eventually lead to death.
A study by the Gladstone Institute shows that a new technology based on CAR-T cell immunotherapy shows great hope in multiple therapeutic areas, especially in the fight against HIV. This new technology is called ConvertibleCAR®, and related research results were published in Cell on October 24, 2019.
The potential pool of HIV is the main obstacle to cure AIDS, and Dr. Warner C. Greene, who is the director of the Center for HIV Cure Research in Gladstone Institute as well as the corresponding author of the paper, has been hoping to target it and clear the virus.
Conventional CAR-T technology is required to transform an immune cell form, that is, cytotoxic T cells, to express antibodies on the surface. The antibody part allows cytotoxic T cells to reside in target cells (such as leukemia cells) and thus to attack and destroy them. Dr. Eytan Herzig of Gladstone Institute, the first author of the paper, said: "The disadvantage of traditional CAR-T is that they are designed to target a single molecule on cancer cells and once injected, they cannot be controlled.
In contrast, ConvertibleCAR technology makes it possible to combine cytotoxic "killer" T cells with any number of antibodies. This is essential for resistance to pathogens such as HIV, because there are hundreds of different variants of HIV. In this paper, scientists have overcome shortcomings by separating targeted antibodies from cytotoxic killer cells.
The modified NKG2D receptor can turn T cells into an effective killer only if it binds to its partner, which is a protein called MIC-A. The researchers trimmed and modified MIC-A so that it can specifically bind to the NKG2D receptor. Then, they fused it to the base of the targeted antibody and created the so-called MicAbody®. In this way, targeting MicAbody can be tightly combined with ConvertibleCAR-T cells.
To eliminate the potential pool of HIV, researchers have been testing a wide range of Broadly Neutralizing HIV-1 Antibodies (bNAb). Herzig explained: “They are called broadly neutralizing antibodies because they can neutralize a large number of strains of virus.”
But bNAb alone is not enough to kill HIV-infected cells. They need the help of killer T cells, and in HIV-infected patients, the problem is that the killer T cells have been exhausted, or the potential reservoir contains viruses that are resistant to these cells. Herzig and Greene believe that by combining bNAb and ConvertibleCAR-T cells, they may obtain the required lethality.
Herzig and Greene tested whether the ConvertibleCAR-Mic-bNAb platform could attack the latent reservoir in the blood of HIV-infected people on antiretroviral therapy (ART). The results prove that the transformable CAR-T cells specifically bind to Mic-bNAbs to kill the infected CD4 T cells, but not the uninfected cells. It was also found that within 48 hours after exposure, more than half of the activated, HIV-expressing cells had been eliminated.
Dr. Eytan Herzig will explain more about this technology in the upcoming webinar held at 3:00 p.m. EDT on June 4th, 2020. The webinar entitled “ConvertibleCAR-T, a highly adaptable CAR-T platform to fight HIV” is sponsored by Creative Biolabs, a leading biotech manufacturer focusing on one-stop CAR-T/NK Cell therapy development service.
One thing interesting about CAR-T cells is that they first appeared in the late 1990s to fight against HIV, but failed. And then traditional CAR-T cells have achieved great success in relieving blood cancers such as lymphoma and childhood leukemia. Now, it comes back to HIV treatment with greater lethality and may even be the key method to overcome AIDS.