CAR-T, a type of immunotherapy may have made its name as the cancer breakthrough of this century, but its roots dig far back to one of humanity’s other terrifying medical enemy: HIV. CAR-T is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient’s blood. Then the gene for a special receptor that binds to a certain protein on the patient’s cancer cells is added in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion. CAR T-cell therapy has been studied and used in the treatment of many types of cancer. Also called chimeric antigen receptor T-cell therapy. However, due to past studies that suggested it might not be usable for HIV treatment, research was never pursued for this disease that is affecting millions globally.
However, Lengtigen, a biotech company based in Gaithersburg, Maryland collaborated with researchers at the Albert Einstein College of Medicine in New York to dust off a blue-sky idea inspired by people who naturally fight off HIV. What if there’s a way to recreate super-powered immune cells in the lab and what the team could do this using the patient’s own immune cells to prevent rejection.
The positive results from that research was published in the Science Translational Medicine Journal.
The team engineered super-immune T cells that are not only resistant to HIV infection, but that can also efficiently hunt down strains widely different in their genetic makeup, including those that normally escape other treatments. Inspired by cancer CAR-T, the team engineered two artificial “claws” onto natural T cells that grab onto the surface of HIV in a death grip. In animal models injected with HIV-infected human cells, the amped-up duo
CAR-T cells suppressed the virus by 97 percent in their spleens, normally a sanctuary for the HIV virus to regroup and bide its time.
“CAR-T cells are making massive advances in cancer, so there’s a huge rationale to expanding their use in the HIV cure effort,” commented Dr. Steven Deeks at UCSF in a phone interview with Thailand Medical News. The study represents a welcomed revival of his initial push for using CAR-T against the virus thirty years ago.
Despite medical researchers best efforts, HIV has been a tough disease to crack. Antiviral therapy helps keep it silenced, but eradicating the virus altogether has been impossible. HIV’s protective shell mutates at an alarmingly high rate, making it remarkably difficult to make vaccines that grasp onto the shell. The virus is also incredibly sneaky: when attacked with anti-viral drugs, it sometimes “plays dead” to sneak past the drug’s actions. These sleeper soldiers form latent reservoirs within tissues, waiting for the perfect chance to re-activate.
So far, only two individuals with HIV seem to be free of the virus. But their treatments were drastic: the individuals required a full-on bone marrow that replaced vulnerable immune cells with HIV-resistant ones. Wiping out HIV wasn’t even the reason for the treatments both had blood cancers that did not respond to chemotherapy and required a total blood stem cell reset. Becoming HIV-free w
as a surprising side effect. For the roughly 80 million people globally living with HIV, bone marrow transplants are not a practical solution.
Thirty years ago, Dr. Steven Deeks turned to a wild, crazy, and novel idea. He genetically altered a batch of T cells to make them a little stronger and a little better at targeting HIV. In other words, he made some CAR-Ts. He inserted a called CD4zeta into different types of T cells. The gene, in theory, allows immune cells to better grab onto HIV. Initially they seemed to work: the cells hung around for up to a year in 24 HIV-positive patients. But subsequent exams found that the CAR-Ts didn’t lower HIV amounts, and in fact made them more
susceptible to HIV infection. His idea, though revolutionary, didn’t pan out.
Despite the setback, CAR-T soon found another home as a breakthrough cancer treatment. Scientists found that T cells engineered with designer proteins on their surface, chimeric antigen receptors, or CARs, could better hunt down markers dotted on the outside of cancer cells. In late 2017, the FDA approved the first CAR-T therapy for certain types of blood cancer. To Dr Steven Deeks, the success of CAR-T and improvement in biotechnologies make it highly attractive to adopt what’s been learned in cancer back to HIV, thus “completing the circle.”
The new study built on Dr Deeks’ experience, though the pioneer wasn’t personally involved. The team started with a simple idea: if one artificial HIV target wasn’t enough, what about two?
Despite the fact that HIV cells frequently change their outer makeup, all viruses contain a protein called gp120 that’s essential for their integrity. The team engineered two CARs that target separate spots on the protein, essentially forming a pair of molecular chopsticks that pinch onto gp120. The first recognizes HIV particles on infected T cells. The second stops HIV from infecting CAR-Ts by blocking the virus’s ability to interact with the super-soldiers. Because of this double-tap, explained study author Dr. Albert Goldstein, it makes it “far more difficult for HIV to mutate around the binders.”
The tag-team immediately proved highly effective in initial experiments. When added to HIV viruses in test tubes, the duoCAR-T wiped out up to 99 percent or more of HIV infection. What’s more, the cells weren’t at all picky in their targeting, efficiently killing off a handful of HIV strains from Europe, Africa, Asia, and America.
As a next proof of concept, the team tested the cells in “humanized” mice. Mice don’t usually get HIV, so to make them mimic human infection the team injected HIV-positive human cells into the mice’s spleens. Some were also given a dose of duoCAR-T.
Compared to control HIV-infected mice, the majority treated ones remained essentially HIV-free for at least 30 days, commented study author Dr. Kim Anthony-Gonda. Even more impressive, the duoCAR-T cells remained healthy even faced with their normal HIV foe, suggesting that unlike Deeks’ pioneering attempt, the cells could effectively fight off the virus themselves.
Although the study only followed the infected mice for 30 days, the near-perfect results have the team’s hopes up. The data “suggest that such potent anti-HIV CAR-T cell effectors have the potential to persist long term and maintain their anti-HIV effects,” the team concluded.
They’re putting their effort where their mouth is. Next year, the team plans to start a small trial that uses CAR-T cells in HIV-infected patients. If successful, the engineered cells should keep the virus completely suppressed even when the patients are taken off drugs, and their T cell count should remain high.
Not everyone is convinced that CAR-T is the way to go for managing HIV. Lessons in cancer therapy clearly paint a nasty picture of side effects: the immune system might hyperactivate from the cell therapy, resulting in tissue damage or even death. Another hiccup is that patients for CAR-T need a dose of chemotherapy first to kill off some natural T cells and make space for the engineered ones. Although the study didn’t find any signs of toxicity, immune or otherwise, it’s hard to predict long-term effects.
The study provided a new look at Car-T immunotherapy and based on the positive results on animal models, the human trails which are set to start next year in 2020 might actually be the start of an actual cure for HIV that many have been trying to discover.
Reference: Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model,Kim Anthony-Gonda, Ariola Bardhi,Alex Ray,Nina Flerin,Mengyan Li,Winfried Krueger,Andrew Worden,Dina Schneider,Zhongyu Zhu,Rimas Orentas,Boro Dropulić ,Science Translational Medicine 07 Aug 2019: Vol. 11, Issue 504, eaav5685 DOI: 10.1126/scitranslmed.aav5685
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