Lara C. Pullen, PhD

December 04, 2013

CHICAGO — Radioimmunotherapy in conjunction with antiretroviral triple therapy can effectively kill HIV-infected cells from patients, a new study has shown.

"The cells are being steadily killed by a dose of radiation," explained Ekaterina Dadachova, PhD, professor of radiology, microbiology, and immunology at the Albert Einstein College of Medicine in the Bronx, New York.

Dr. Dadachova presented the research to an excited audience here at the Radiological Society of North America 99th Scientific Assembly and Annual Meeting. She began her talk by reminding the audience that the conference started on December 1, World AIDS Day.

The safety of radioimmunotherapy is well established in the field of oncology, where tumor cell burdens are approximately 1000 times greater than those seen in HIV patients being treated with triple therapy. This makes HIV a comparatively light load for radioimmunotherapy, according to those most familiar with the technique.

Current treatment options for HIV include antiretrovirals, which can dramatically increase a patient's lifespan and has transformed HIV from an acute disease. "HIV is now a chronic disease, but people are still dying from it and there is still no cure," Dr. Dadachova said.

Medications suppress viral reproduction, but they do not kill infected cells. Antiretrovirals also have a host of problems, including high cost, toxicity, nonadherence, and drug resistance.

Most important, viremia returns after treatment cessation. This is because both cellular and anatomic reservoirs of HIV in the body maintain the infection.

It has fantastic potential.

At the cellular level, even with antiretrovirals, the patient's body contains long-lived cell populations that are infected with HIV and are capable of surviving for prolonged periods of time. Resting CD4+ T-cells, macrophages, dendritic cells, and hematopoietic cells can all serve as reservoirs for HIV.

Anatomically, HIV also persists in the brain, and this has traditionally been a very difficult area for HIV therapeutics to access.

The world needs a strategy for eradicating HIV, said Dr. Dadachova. She then proceeded to describe her team's strategy using radioimmunotherapy.

The approach is effective against HIV-infected cells because it binds to a specific antigen and kills the cells. To be successful as a therapy, it requires an antigen target that in no way resembles a human antigen. If such an antigen can be found, then "1 or 2 hits per cell is enough to destroy the cell," explained Dr. Dadachova.

Her team used the HIV antigen gp41 to generate the 2556 antibody that binds specifically to HIV-infected cells.

Radiolabeled human antibody binds to the viral gp41 protein expressed on the surface of the HIV-infected lymphocyte and the cell is killed with alpha radiation.

The researchers previously used gp41 radioimmunotherapy in mice with severe combined immunodeficiency that were injected with infected human cells (PLoS One. 2012;7:e31866). "We are basically able to eliminate the HIV-infected cells in those mice," Dr. Dadachova said enthusiastically. More important, they were able to eliminate HIV-infected cells in the brains of the mice.

Although the team's success with mice was exciting, she noted that they still did not know whether radioimmunotherapy would work in patients being treated with antiretroviral therapy. No one could say what the interaction between radioimmunotherapy, HIV, and antiretrovirals would look like. Would the suppressed viral replication also suppress the expression of gp41 below the level needed for radioimmunotherapy?

"That's where the Bill and Melinda Gates Foundation came in," she said. "They funded our study."

This year, Dr. Dadachova and her team performed an ex vivo study on clinical samples. They found that radioimmunotherapy killed the infected patient's lymphocytes over a full range of doses.

They also used an in vitro model to demonstrate that the radiolabeled antibody crosses the blood–brain barrier without disturbing the tight junctions of the cells.

"It has fantastic potential," said Gary Whitman, MD, professor of radiology at the University of Texas M.D. Anderson Cancer Center in Houston.

Dr. Dadachova will next be partnering with physicians in South Africa to enroll patients there in the first radioimmunotherapy clinical trial. She said she expects the first results by the end of 2014. She also reported that she is applying to the National Institutes of Health for funding to continue the research in the United States.

The treatment regimen will likely consist of a single injection of radioimmunotherapy, she explained. Because bismuth-213 is a very short-lived isotope, all radioactivity will be gone from the patient in 4 hours. Follow-up testing will reveal whether the patient rebounds and requires another treatment.

Many in the room said the precedence of radioimmunotherapy in the treatment of cancer fuels their hope that people will truly have something to celebrate next World AIDS Day.

Dr. Dadachova and Dr. Whitman have disclosed no relevant financial relationships.

Radiological Society of North America (RSNA) 99th Scientific Assembly and Annual Meeting: Abstract SSK12. Presented December 3, 2013.


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