A total of nine changes were made to TAG’s listing for the February 2024 update.
New Additions
Two new clinical trials have been added, both not yet open for enrollment.
Researchers at the City of Hope Medical Center in Los Angeles are planning to initiate a trial of a novel approach to chimeric antigen receptor (CAR) T cell therapy in people with HIV. CAR T cells are a form of gene therapy based on modifying the receptors on the surface of T cells that facilitate recognition of a given target (e.g. part of HIV or other pathogens, or a cancerous cell). T cells are extracted from individuals, genetically modified in the laboratory to endow them with a particular type of receptor or receptors, then expanded and reinfused. Several CAR T cell therapies that target cancers are licensed for use.
The City of Hope study will focus on sampling T cells from study participants that specifically target cytomegalovirus (CMV), a very common virus that most people carry for life. These CMV-specific T cells will then be genetically modified to equip them with an additional receptor that recognizes part of the outer HIV envelope. The rationale is that the low levels of CMV present in a person’s body will help stimulate and maintain the modified CMV-specific CAR T cells, allowing them to persistently target HIV-infected cells via the secondary receptor.
One caveat is a recently emerging concern that, in some rare cases, CAR T cells approved for cancer therapy can become cancerous themselves as a result of the gene modification. An update from the Food and Drug Administration (FDA) was published yesterday in the New England Journal of Medicine. Far fewer people have received experimental CAR T cells targeting HIV (none are approved), and while the same concern may apply there are studies that have conducted extended follow up without any cases of T cell cancers observed to date.
TAG has contacted the FDA to ask about relevance to HIV and whether new studies like those proposed by City of Hope could be delayed as the problem is investigated - any response will be covered in next month's update. There are newer approaches to performing CAR T cell gene modification that don’t involve lentiviral vectors, which offer hope that a new generation of products can be developed that carry no risk of cancerous transformation.
The second new study is being led by Casper Rokx at the Erasmus Medical Center in the Netherlands, with support from Aidsfonds. The phase I/II trial will take place at multiple sites and aims to build on evidence from a prior study that the antiparasitic drug pyrimethamine has HIV latency-reversing activity.
A total of 49 participants will be recruited and given single doses of pyrimethamine, the HDAC inhibitor panobinostat and the immunomodulator lenalidomide either alone or in the following dual combinations: panobinostat + lenalidomide, panobinostat + pyrimethamine, or lenalidomide + pyrimethamine.
Investigators will assess levels of HIV RNA production by latently infected cells after dosing, and any change in the size of the HIV reservoir between the baseline visit and the end of study follow up (120 days later).
While not quite a new addition, an ongoing phase I trial of the therapeutic HIV vaccine candidate ICVAX is now entered into the clinicaltrial.gov registry, allowing us to update a previous link. For additional information on the vaccine and study, see the blog post on the August update to TAG’s listing.
Updates to Enrollment Status
One observational study closed for enrollment this month, also led by Casper Rokx in the Netherlands. CHRONO has created a cohort of people on antiretroviral therapy (ART) who are contributing samples for laboratory studies of the HIV reservoir and candidate therapeutic approaches.
Completed Studies
Two clinical trials in the listing have officially ended and been moved to the completed studies table.
An ACTG study conducted by Eileen Scully and colleagues specifically enrolled postmenopausal cisgender women with HIV to investigate the effects of the candidate HIV latency-reversing agent vorinostat administered with or without tamoxifen, a drug which modulates estrogen receptors on cells (including CD4+ T cells). Results were published in 2022, finding no enhancing effect of tamoxifen on HIV latency reversal but, importantly, establishing “both the feasibility and necessity of investigating novel HIV cure strategies in women living with HIV.”
A long-term follow up protocol for people with HIV who participated in studies of a gene therapy developed by Sangamo Biosciences has been stopped. The clinicaltrials.gov registry record explains that no safety signals have emerged over 7.5 - 13.5 years since administration. The Sangamo candidate involved extracting CD4 T cells from participants and genetically modifying them to abrogate expression of the CCR5 co-receptor that most HIV strains use as a route into target cells. The modified CD4 T cells were then expanded in the laboratory and reinfused. Sangamo has discontinued development, but a small biotech company named RORA Biologics is now pursuing a potentially improved version that targets a subset of CD4 T cells called T stem cell memory cells.
New Links to Study Results
Three of the studies in the listing have had links added to newly published results.
Karine Dubé and colleagues conducted in-depth interviews with participants in a small cure-related clinical trial at the University of California San Francisco (UCSF) that involves a complex combination of different components (therapeutic HIV vaccines, broadly neutralizing antibodies and a TLR9 agonist). The study also includes an extended analytical treatment interruption (ATI). The paper is available open access in the journal HIV Research & Clinical Practice.
The informative interviews with seven of the 10 participants capture a range of individual responses, but anxiety related to interrupting ART during the ATI was reported by six out of seven. Trust in the research team was high, with all participants already involved in the UCSF SCOPE cohort. Several issues related to communication to sexual partners about viral load rebound during the ATI were identified.
The participant who controlled viral load for the longest time off ART, around 18 months, expressed the feeling of being in a limbo state during that period and was uncomfortable with the degree of uncertainty about how the control was being mediated. Examples of extended post-ART control in cure-related research offer some encouragement to the field, but it’s also important to appreciate that the experiences of the individuals concerned may be more complex, particularly as post-treatment control has become viewed as a potentially more achievable outcome than complete clearance of HIV.
Jonathan Li led an investigation into predictors of viral load rebound among people interrupting ART in the ACTG A5345 study, which was published in JCI Insight on February 8th. The key findings were that predictors of the time to viral load rebound were different among participants who started ART early compared to during chronic HIV infection. Residual levels of viral load (measured by an ultrasensitive test) were the strongest predictor in the former group, whereas in the latter group it was levels of intact HIV DNA. The paper is open access.
Results from a trial combining the latency-reversing agent vorinostat with an adoptive immunotherapy in people on ART have been published in the Journal of Infectious Diseases by Cynthia Gay and colleagues. The immunotherapy is called HIV-1 Antigen-Expanded Specific T-Cell Therapy (HXTC): T cells targeting HIV are sampled from participants, expanded in the laboratory, and then reinfused.
The interventions proved safe and three participants who received the highest dose of transferred T cells showed some evidence of a decline in the size of their HIV reservoir as measured by the quantitative virus outgrowth assay (QVOA). However, the researchers emphasize that these declines were not greater than 6-fold, which is the magnitude of difference they’ve previously identified as necessary to rule out variability in the test as the cause. The results offer some tentative support for the idea of combining latency reversal with T cell therapies, but the authors note that “even if these trends were validated in a larger, controlled study, we would still conclude that achieving an HIV cure requires more effective latency reversal coupled with efficacious immune interventions.”
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