Can HIV Docs Learn Something From Hem-Oncs?
By Bruce Buckley
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Dr. June spoke at the 2017 annual Conference on Retroviruses and Opportunistic Infections . His talk focused mainly on chimeric antigen receptor (CAR) T-cell therapy for adult and pediatric lymphoblastic and lymphocytic leukemias, as well as its promise for inducing functional cures in people with HIV.
CAR T-cell immunotherapy involves collecting a patient’s autologous T cells and engineering them through various gene transfer technologies to insert a CAR—a synthetic molecule with antibody specificity that is expressed on the surface of T cells. These reprogrammed cells are infused into a patient where they bind to any cancer or HIV cell with the specific antibody.
The cell-killing effect can have a long-lasting effect on the immune system. In 2012, researchers went back and examined antiretroviral-treated HIV patients who had entered three Phase I and II CAR T-cell trials that were launched 15 years earlier. They found, he said, that the patients were “still engrafted” with both CD4 and CD8 CAR T cells (Sci Transl Med 2012;4[132]:132Ra53).
“The half-life of those cells was greater than 17 years,” he said. “So essentially, one infusion of gene-modified T cells can last a lifetime. That’s one reason I think we’ll be able to install very potent HIV-specific immunity in patients by modifying T cells and/or stem cells.” Moreover, he said, there were “no integration-related toxicities” associated with CAR T-cell therapy.
Dr. June described another trial by researchers from the University of Pennsylvania, “the first trial with genetic editing we did with Sangamo BioSciences.” It was a small Phase I study designed to ascertain safety and feasibility of inducing acquired genetic resistance to HIV infection that would mimic the inherited resistance of people with the CCR5-delta32 mutation. Twelve patients with chronic aviremic HIV infection who were receiving highly active antiretroviral therapy were enrolled (N Engl J Med 2014;370[10]:901-910). Using zinc-finger nucleases (ZFNs), the researchers introduced a double-stranded disruption in DNA at the site of the CCR5 gene, which encodes a coreceptor for HIV entry. The patients were given a single infusion of autologous CD4-enriched T cells that had been modified at the CCR5 site by ZFNs.
The results of that trial, Dr. June said, showed that the treatment “was safe in all patients. The cells persist in our first patient treated in 2009, now more than five years. So gene-edited cells can last for a very long timescale.” He added that data presented in the paper “supports the mechanism that it confers a permanent antiviral effect on the infused cells. It’s the first example of gene editing to induce disease resistance. And I think there are a lot of ways now to make people naturally CCR5 homozygous.”
Despite the promise, cell therapy research related to HIV remains sparse. Dr. June noted that there were 161 CAR T-cell clinical trials for cancer listed at ClinicalTrials.gov on Feb. 14, most them in the United States and China.
“What about HIV?” he said. “Unfortunately, it’s a big goose egg: zero. This needs to change. Right now my message would be that we need to surf off what’s being done in the cancer field and apply those learnings to HIV.”
Dr. June noted that more potent CARs are available today than the “one we tested in the late 1990s: the CD4zeta” (Blood 2000;96[3]:785-793). For example, he listed five recent studies that have addressed HIV therapy using either T cells or stem cells (see box). “There are not more than a handful of laboratories doing this at this point because it’s very difficult to get funding.
“We need a cancer moonshot but applied to HIV in order to use these tools,” he said.
(snip)
Dr. June spoke at the 2017 annual Conference on Retroviruses and Opportunistic Infections . His talk focused mainly on chimeric antigen receptor (CAR) T-cell therapy for adult and pediatric lymphoblastic and lymphocytic leukemias, as well as its promise for inducing functional cures in people with HIV.
CAR T-cell immunotherapy involves collecting a patient’s autologous T cells and engineering them through various gene transfer technologies to insert a CAR—a synthetic molecule with antibody specificity that is expressed on the surface of T cells. These reprogrammed cells are infused into a patient where they bind to any cancer or HIV cell with the specific antibody.
The cell-killing effect can have a long-lasting effect on the immune system. In 2012, researchers went back and examined antiretroviral-treated HIV patients who had entered three Phase I and II CAR T-cell trials that were launched 15 years earlier. They found, he said, that the patients were “still engrafted” with both CD4 and CD8 CAR T cells (Sci Transl Med 2012;4[132]:132Ra53).
“The half-life of those cells was greater than 17 years,” he said. “So essentially, one infusion of gene-modified T cells can last a lifetime. That’s one reason I think we’ll be able to install very potent HIV-specific immunity in patients by modifying T cells and/or stem cells.” Moreover, he said, there were “no integration-related toxicities” associated with CAR T-cell therapy.
Dr. June described another trial by researchers from the University of Pennsylvania, “the first trial with genetic editing we did with Sangamo BioSciences.” It was a small Phase I study designed to ascertain safety and feasibility of inducing acquired genetic resistance to HIV infection that would mimic the inherited resistance of people with the CCR5-delta32 mutation. Twelve patients with chronic aviremic HIV infection who were receiving highly active antiretroviral therapy were enrolled (N Engl J Med 2014;370[10]:901-910). Using zinc-finger nucleases (ZFNs), the researchers introduced a double-stranded disruption in DNA at the site of the CCR5 gene, which encodes a coreceptor for HIV entry. The patients were given a single infusion of autologous CD4-enriched T cells that had been modified at the CCR5 site by ZFNs.
The results of that trial, Dr. June said, showed that the treatment “was safe in all patients. The cells persist in our first patient treated in 2009, now more than five years. So gene-edited cells can last for a very long timescale.” He added that data presented in the paper “supports the mechanism that it confers a permanent antiviral effect on the infused cells. It’s the first example of gene editing to induce disease resistance. And I think there are a lot of ways now to make people naturally CCR5 homozygous.”
Despite the promise, cell therapy research related to HIV remains sparse. Dr. June noted that there were 161 CAR T-cell clinical trials for cancer listed at ClinicalTrials.gov on Feb. 14, most them in the United States and China.
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Dr. June noted that more potent CARs are available today than the “one we tested in the late 1990s: the CD4zeta” (Blood 2000;96[3]:785-793). For example, he listed five recent studies that have addressed HIV therapy using either T cells or stem cells (see box). “There are not more than a handful of laboratories doing this at this point because it’s very difficult to get funding.
“We need a cancer moonshot but applied to HIV in order to use these tools,” he said.
