Drugs work stunningly well to control HIV—but not in everyone, and not without side effects. That’s why a small cadre of patients known as elite controllers has long fascinated researchers: Their immune system alone naturally suppresses HIV for decades without drugs. Now one team, inspired by success in mice, hopes to endow HIV-infected people with tailormade immune cells that target HIV, in effect creating elite controllers in the clinic.

The immune strategy has risks, but it builds on increasingly popular cancer treatments with T cells engineered to have surface proteins, called chimeric antigen receptors (CARs), that can recognize markers on the surfaces of tumor cells and destroy the cancer. Such CAR T cells can also be tailored to identify and eliminate HIV-infected cells. This approach was tested in HIV-infected humans long before CAR T cells proved their worth against cancer, but it roundly failed. The field wants “to move what’s been learned from cancer back to HIV, completing the circle,” says Steven Deeks, an HIV/AIDS clinician at the University of California, San Francisco, who first tested a CAR T cell against the virus in the late 1990s.

The new study—conducted by researchers from the University of Pittsburgh in Pennsylvania; the biotech company Lentigen in Gaithersburg, Maryland; and the Albert Einstein College of Medicine in New York City—uses a far more sophisticated CAR approach than the one Deeks tested. “It’s promising and seems to be more potent than what’s been tried in the past,” says stem cell biologist Hans-Peter Kiem, who has tested CAR T cells in leukemia and lymphoma patients at the Fred Hutchinson Cancer Research Center in Seattle, Washington.

For the new work, published online this week in Science Translational Medicine, the researchers engineered T cells to include genes encoding two kinds of CARs, each targeting a different part of HIV’s surface protein. In test tube studies, this “duoCAR T” cell powerfully killed white blood cells infected with a diverse array of HIV variants, the group reports.

The team also gave near simultaneous injections of CAR T cells and HIV-infected human cells to the spleens of mice with a “humanized” immune system. (Rodents cannot normally be infected with the AIDS virus.) When the group harvested spleens from the mice a week later, five of six mice had no detectable HIV DNA and their average viral levels had dropped 97.5%.

The group tested several other variations of CAR T cells in subsequent mouse studies to find the best combination of components. Its hope is that these CAR T cells could turn more people into elite controllers. Over time it might even cure them.

Immunovirologist Harris Goldstein of Albert Einstein, who conducted the mouse studies, says the duoCAR T cells promise to overcome a problem that hampered similar efforts in the past: The virus can easily change regions of its surface protein and dodge recognition by the engineered killer cells. By simultaneously binding to multiple regions on this protein, the dual receptor approach “makes it far more difficult for HIV to mutate around the binders,” Goldstein says.

In addition to putting genes for the CARs into the killer T cells—which are distinguished by the surface protein CD8—the researchers also modified CD4 T cells. CD4 cells, which regulate immune responses, are HIV’s favorite target, and their destruction is the hallmark of AIDS. The researchers found that the CD4 cells engineered to carry the CARs were highly resistant to HIV, probably because the CAR T binders disrupt the complicated infection process, in which HIV first connects to CD4 receptors and then attaches to a second receptor.

What works in a mouse or a test tube may not work in people, however, and CAR T cell treatment can be dangerous. “I’m not sure this is ready for patients without malignancies,” Kiem says. It requires toxic chemotherapy to kill some of a patient’s natural T cells to make “space” for the new ones to engraft. What’s more, in some cancer patients, CAR T cells have so supercharged the immune system that the treatment has destroyed organs.

Deeks hopes to run a small study of the new CAR T cells in HIV-infected people next year, using a minimal chemotherapy treatment beforehand. The study will enroll people who are controlling their infections with antiretrovirals, have them stop taking the drugs and see whether the infused CAR T cells can keep HIV suppressed. “CAR T cells are making massive advances in cancer, so there’s a huge rationale to expanding their use in the HIV cure effort,” Deeks says.

He acknowledges that the risks of CAR T cells may be less acceptable to HIV-infected people doing well on antiretrovirals than to cancer patients who have few other options. The upside is that if it works, they may be able to stop taking antiretrovirals for prolonged periods or perhaps forever—and they can always return to the drugs if it fails. Deeks is confident he’ll find people willing to take the gamble, if only to further research into a promising idea and help others living with the virus.

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Long before I became president and director of Seattle’s Fred Hutchinson Cancer Research Center, I learned all-too-well the link between infectious disease and cancer.

As a medical student at the University of California, San Francisco during the 1980s, I witnessed the early days of the AIDS epidemic. Young men with HIV were dying in that city by the thousands of unusual opportunistic infections such as pneumocystis pneumonia and rare cancers such as Kaposi sarcoma.

I worked at San Francisco General Hospital on a medical team with Dr. Sue Desmond-Hellmann, who was also profoundly influenced by the suffering there; she went on to a successful career in oncology and infectious disease. Her star kept rising. At the biotechnology pioneer Genentech, she was responsible for the development of a plethora of novel cancer drugs including monoclonal antibodies such as trastuzumab, or Herceptin, for breast cancer and rituximab for B-cell malignancies. Then she returned to lead UCSF as chancellor, and today she is chief executive officer of our good neighbors in Seattle, the Bill & Melinda Gates Foundation.

While our paths have crossed frequently over the years, it was particularly meaningful recently when we met again — this time in, of all places, Kampala, Uganda.

For two pivotal years beginning in 1989, Sue had lived in that city studying HIV/AIDS and cancer at the Uganda Cancer Institute. Last month, she revisited Kampala, and together we walked through the UCI-Fred Hutch Cancer Centre, which is jointly operated by UCI and Fred Hutch’s Global Oncologyprogram. It is a world-class facility with a wonderful staff; and it is a place where the link between infectious diseases and cancer is witnessed daily.

Both of us found it humbling and inspiring to observe the great work being done by many young researchers working in challenging situations where so many cancer patients are also infected with HIV.

In sub-Saharan Africa, 33% of all cancers are caused by infectious agents; and HIV, which severely impairs a person’s immune system, can make that person even more prone to infection by other viruses that can lead to cancers. For example, about 85% of patients at UCI with Kaposi sarcoma — caused by a herpes virus that existed long before AIDS — are HIV-positive as well.

Kaposi sarcoma often presents as dark or purple lesions on the skin of individuals infected with HIV. Until effective antiviral drugs against HIV were developed, it was literally the face of AIDS in the United States. It still takes a toll in Uganda, despite a laudable program to provide these drugs to people there living with HIV.

While at UCI-Fred Hutch, Sue and I met a young woman, Margaret Sunday, who had arrived there with severe Kaposi sarcoma lesions covering her feet and legs. She had been under care for HIV and had been taking antiviral drugs. Sadly, despite this medical attention, her cancer had not been diagnosed early and had gone untreated.

It was immediately apparent that we are still missing something in the screening and treatment of HIV in sub-Saharan Africa. In the United States, HIV screeners also look for cancers. We look for other viral infections, like human papillomavirus, or HPV, that can lead to cervical cancer, understanding that the risk of cervical cancer in women with HIV — nearly all of whom also have HPV — is increased more than fivefold. For patients in the US with HIV, where treatment is widely available, the leading cause of death is no longer opportunistic infection as it was in the 1980s — rather, it is cancer. If we treat HIV but not the cancer, it is as if we are treating half the patient.

In Uganda, I believe we are making progress. The UCI-Fred Hutch Collaboration expands local capacity in scientific research, training and patient care, serving as a great model for addressing global health challenges.

Because of the challenges we face in treating cancer with chemotherapy and radiation therapy in a resource-limited environment, it is critically important that we reduce the cancer burden on patients in this region. We must strengthen all facets of cancer and HIV care — including screening, early diagnosis and all stages of treatment. We must strengthen the bonds between cancer prevention and infectious disease prevention. That is why UCI-Fred Hutch nurses who screen for HIV are also trained to tie the screening for cervical cancer to HIV testing and care.

I was gratified to see Sue reunite with some of the amazing people she worked with in Kampala in the 1980s. We saw staff equipped with advanced facilities and technologies that did not exist or were unthinkable three decades ago: a specimen-receiving lab, a histopathology lab for processing biopsies, a lab for genomic sequencing.

Sue and I also visited the medical records room containing paper records stacked to the ceiling dating back more than 50 years to the inception of the UCI. Remarkably, UCI-Fred Hutch staff pulled several charts from 1989–1990 with handwritten notes by Sue herself — very comprehensive notes I might add, with complete differential diagnoses included!

As vaccine programs are a central focus of the Gates Foundation, we further discussed our efforts to ensure broad vaccination with HPV vaccines. At the Hutch we are especially focused on HPV vaccines as they were developed with the help of insights from investigators like Dr. Denise Galloway, who holds the Paul Stephanus Memorial Endowed Chair. These were but a few of the truly memorable “full-circle” moments during our visit.

We will continue to work in close collaboration with our African colleagues to gain ground against both cancer and infectious diseases. We are all committed to using our understanding of the linkage between infectious disease and cancer to better treat — and prevent — them both.

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