An HIV immunotherapy study with proof of concept passes the Phase 1 safety trial

Preliminary results from a Phase I clinical trial demonstrated the safety and tolerability of a cell therapy involving the ex vivo expansion of T cells and their subsequent infusion in individuals infected with HIV previously treated with antiretroviral therapy. The study appears on September 21 in the journal Molecular Therapy.

"This study aims to find a way to re-educate the immune system to better combat HIV infection," said David Margolis, co-senior author of the University of North Carolina (UNC) at Chapel Hill. "We found that this approach of re-educating immune cells and re-infusing them was safe, which was the main focus of the study.The data from this trial will continue to help us design immunotherapies. improved against HIV. "

Having changed the game for patients living with HIV, ART transformed what was once a death sentence into a chronic disease. But this is not a cure, and the virus persists in a latent reservoir that remains hidden from the immune system. Approaches using pharmacological agents to reverse HIV latency to induce a latent virus to express a viral protein could make this reservoir vulnerable to T cells. However, the specific immune response to HIV existing in People treated with ART are insufficient to eliminate persistent infection, even in the presence of latency reversal agents that induce HIV expression.

Adoptive cell therapy is a safe way to exploit T-cell responses to fight HIV. This procedure involves collecting T cells from a patient, growing them in the laboratory to increase their numbers, and then handing them to the patient to help the immune system fight the disease. Previous approaches to adoptive T-cell therapy for HIV have limited efficacy due to multiple factors. Since these previous attempts, the field of adoptive T-cell therapy has made significant progress, mainly in the field of oncology, which could help overcome some of the pitfalls encountered with earlier approaches to T therapy on HIV. The T cells generated by these sophisticated expansion methods have been safe and well tolerated, while being very effective.

"Before we can combine this approach with treatments designed to eliminate HIV in order to improve the immune response, we must first establish that this approach to immunotherapy is safe," says Dr. 39, co-senior author of the study. Catherine Bollard of the National Children's Health System. "We have a long-standing experience in treating patients with virus-specific T-cells targeting latent viruses such as the Epstein-Barr virus and cytomegalovirus, so we were very excited to work with them. UNC team to adapt this virus-specific T therapy to the HIV approach. "

In the small proof of concept study, Margolis, Bollard and their collaborators produced ex vivo-expanded HIV-specific T cells (HXTC); their long-term goal was to use HXTC as part of a strategy to eliminate persistent HIV infection. The researchers administered two HXTC infusions over a two-week period to six HIV-infected participants whose viral load had been reduced to an undetectable level by antiretroviral therapy.

This treatment was well tolerated and had few adverse events. In addition, two patients experienced a detectable increase in T cell-mediated antiviral activity after both infusions, although the clinical significance of this mild to modest impact is unknown. In the overall assessment of participants, the research team found no overall improvement in the magnitude of the HIV-specific immune response. This could be due to the low dose of both infusions and the lack of strategies to promote T-cell expansion once they are present in the body.

There was also no decrease in the size of the latent reservoir, probably due to the lack of treatments such as latency inversion agents, designed to disrupt the reservoir and induce a recognizable expression of HIV proteins that trigger immune responses. In the future, a crucial question will be whether HXTC therapy associated with latency reversers can deplete the HIV reservoir to a measurable extent by current HIV latency tests. A study of HXTC in combination with vorinostat agent of the latency reversal agent is currently being evaluated in an ongoing clinical trial.

"This is a promising breakthrough for the field," says UNC's first author Julia Sung, although she also warns people against excessive interpretation of the results. "The study has not cured HIV and should not be interpreted as such, but we are also very encouraged by the safety data, so it should not be considered discouraging, which opens the way for the next step. , namely an immunotherapy approach with a latency reversal therapy to awaken HIV out of its latent state, where it is invisible to the immune system, then eliminate by immunotherapy. "

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More information:
Molecular Therapy, Sung et al .: "HIV-specific ex-Vivo-widened T-cell therapy (HXTC): feasibility, safety and efficacy in HIV-infected and HIV-infected individuals" https://www.cell.com/ molecular-family-therapy / molecular therapy / fulltext / S1525-0016 (18) 30400-3, DOI: 10.1016 / j.ymthe.2018.08.015