Report From the 2017 IAS HIV Cure and Cancer Forum
The IAS HIV Cure & Cancer Forum was held at the renowned cancer research center Institut Curie in Paris on July 22 & 23 of this year. A report from the meeting, authored by Genevieve E. Martin, José Alcami, Jean-Phillipe Spano and Anna Laura Ross, has just been published in the open access Journal of Virus Eradication, and many of the slide presentations are posted to the Forum website.
Some of the intersections between the two disciplines were described in a presentation by Olivier Lambotte at last year's IAS Towards an HIV Cure Symposium in Durban, South Africa, and the 2017 event expanded on the theme. Similarities include the need to identify and target relatively rare, hard-to-access cells for elimination - a task which requires gaining an understanding of the reasons why natural immune responses are ineffective and the development of strategies to bolster immunity against the cells of interest (whether cancerous or latently infected by HIV).
As the meeting report notes, many approaches being pursued as cancer therapeutics are also being studied in the context of HIV cure research, including immune checkpoint inhibitors, cytokine therapies, genetically modified chimeric antigen receptor (CAR) T cells and other gene therapies.
The coverage of the presentations offered in the report is fairly comprehensive, but there are some additional pieces of information that may be of interest. There was a presentation by Francoise Villinger from the University of Louisiana at Lafayette describing the use of radiolabeled anti-virus antibodies to image the locations of SIV expression in the bodies of macaques, and a clinical trial is due to open soon in Australia that will explore a similar approach in humans using a radiolabeled version of the broadly neutralizing antibody 3BNC117.
Larry Corey from the Fred Hutchinson Cancer Research Center gave an excellent talk on the potential of CAR T cells, describing both the positive results in cancer (a CAR T cell therapy for acute lymphoblastic leukemia became the first to be approved by the FDA not long afterward) and some of the issues that have arisen with adverse events. In the context of HIV cure research, Corey highlighted a number of factors he considers likely to be important, including:
- The provision of HIV-specific CD4 T cell help to CAR CD8 T cells using CD4 T cells that have been modified to resist HIV infection.
- Targeting of CAR T cells to HIV reservoir sites such as lymph node B cell follicles (some experiments addressing this issue using CD8 T cells modified to express the trafficking receptor CXCR5 have already been conducted in SIV-infected macaques).
- Equipping CAR T cells with receptors that allow them to recognize and kill HIV-infected cells quickly after the virus is reactivated (a recently published study from the research group of Brad Jones suggests that the HIV Nef protein may be a particularly important target for this purpose).
- Ensuring CAR T cells can persist at the sites where they are needed.
- Avoiding the adverse events that have been observed in some cancer studies, most notably cytokine release syndrome and neural toxicity.
Corey focused on the potential of directing CAR T cells to HIV antigens, but a recent cancer trial may also raise the possibility of targeting cellular receptors that are preferentially expressed by latently infected CD4 cells. In a paper published in the Journal of Clinical Investigation, researchers describe promising results obtained with CAR T cells engineered to recognize CD30, a receptor expressed by non-Hodgkin's lymphomas. Ongoing work by the laboratory of Timothy Heinrich (as yet unpublished, but briefly described in a summary for the supporting NIH grant) has identified CD30 as a possible marker for CD4 cells containing latent HIV. While Heinrich's group is initially looking at brentuximab vedotin, an FDA-approved antibody-drug conjugate that targets CD30 but has some notable toxicities, CAR T cells could offer an alternative means to the same end.
One presentation that is not covered in the meeting report was delivered by Marina Cavazzana from Hôpital Necker in Paris. Cavazzana is working on a novel approach to promoting immune reconstitution by accelerating production of naïve T cells from the thymus. At one time, this was an area of intense interest in HIV research, and a number of candidate therapies were evaluated (keratinocyte growth factor is among the examples) but results proved disappointing and there has been little activity related to the thymus in recent years. Persistent deficits in naïve T cell levels are still a concern, however, particularly for individuals who experience suboptimal CD4 T cell recovery on antiretroviral therapy (immunologic non-responders or INRs), so a candidate treatment could still have relevance.
Cavazzana's strategy involves the use of a laboratory culture method to generate T cell precursors from stem cells, mimicking the early steps of maturation that would normally occur in the thymus. In experiments where these lab-generated T cell precursors were infused into immunodeficient mice, reconstitution of mature naïve T cells was significantly accelerated. Phase I/II clinical trials involving adults receiving stem cell transplants for cancers and children with primary immunodeficiencies are due to begin in January 2018. Cavazzana noted that there is also the potential to modify the T cell precursors with gene therapy prior to infusion.
A lively roundtable discussion on clinical trial design and participation is summarized in the meeting report (see box 1), but video of the presentation by Michael Louella from the University of Washington AIDS Clinical Trials Unit/defeatHIV is also available on the defeatHIV Youtube channel.
Panel participant Thomas Uldrick from the National Cancer Institute drew attention to an important initiative involving the U.S Food & Drug Administration, American Society of Clinical Oncology and Friends of Cancer Research that is attempting to expand eligibility criteria for trials of novel anticancer agents to include HIV-positive people. Uldrick pointed out that the median time from phase I to an HIV-specific study for novel anticancer agents (6.3 years) is only a few months shorter than the average time from phase I to FDA approval, a problem that urgently needs to be addressed given that the prognosis for people with HIV is so much improved due to ART. Uldrick encouraged attendees to spread the word about the initiative.
In addition to the new report, the IAS blog has also published a commentary on the meeting by Geneviève Almouzni, Director of the Institut Curie Research Center and CNRS Research Director, timed to coincide with World Cancer Research Day.
[Note from TheBody.com: This article was originally published by Treatment Action Group on Sept. 29, 2017. We have cross-posted it with their permission.]