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HIV-specific CAR T cells return to the clinic
Christopher W. Peterson1,2
1Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
2Department of Medicine, University of Washington, Seattle, Washington, USA.
Address correspondence to: Christopher W. Peterson, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Mail Stop D1-100, PO Box 19024, Seattle, Washington 98109-1024, USA. Phone: 206.667.6646; Email: cwpeters@fhcrc.org.
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Published October 1, 2021 - More info
J Clin Invest. 2021;131(19):e153204. https://doi.org/10.1172/JCI153204.
© 2021 American Society for Clinical Investigation
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Abstract
BACKGROUND Chimeric antigen receptor (CAR) T cells have emerged as an approach to treat malignant tumors. This strategy has also been proposed for the treatment of HIV-1 infection. We have developed a broadly neutralizing antibody–derived (bNAb-derived) CAR T cell therapy that can exert specific cytotoxic activity against HIV-1–infected cells.METHODS We conducted an open-label trial of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of bNAb-derived CAR T cell therapy in individuals infected with HIV-1 who were undergoing analytical interruption of antiretroviral therapy (ART).RESULTS A total of 14 participants completed only a single administration of bNAb-derived CAR T cells. CAR T cell therapy administration was safe and well tolerated. Six participants discontinued ART, and viremia rebound occurred in all of them, with a 5.3-week median time. Notably, the cell-associated viral RNA and intact proviruses decreased significantly after CAR T cell treatment. Analyses of HIV-1 variants before or after CAR T cell administration suggested that CAR T cells exerted pressure on rebound viruses, resulting in a selection of viruses with less diversity and mutations against CAR T cell–mediated cytotoxicity.CONCLUSION No safety concerns were identified with adoptive transfer of bNAb-derived CAR T cells. They reduced viral reservoir. All the rebounds were due to preexisting or emergence of viral escape mutations.TRIAL REGISTRATION ClinicalTrials.gov (NCT03240328).FUNDING Ministry of Science and Technology of China, National Natural Science Foundation of China, and Department of Science and Technology of Guangdong Province.
Authors
Bingfeng Liu, Wanying Zhang, Baijin Xia, Shuliang Jing, Yingying Du, Fan Zou, Rong Li, Lijuan Lu, Shaozhen Chen, Yonghong Li, Qifei Hu, Yingtong Lin, Yiwen Zhang, Zhangping He, Xu Zhang, Xiejie Chen, Tao Peng, Xiaoping Tang, Weiping Cai, Ting Pan, Linghua Li, Hui Zhang
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Next steps for HIV CAR T cell therapies
Much remains to be learned regarding the requirements for an effective CAR T cell strategy for persistent HIV infection. Many will continue to highlight similarities and opportunities for synergy with CAR T cells for cancer. It is increasingly clear that the local immune environment, the frequency of antigen-expressing target cells, and/or the density of antigen on the surface of each target (Figure 1) are important considerations that must be addressed. Due to the well-characterized persistence of HIV-infected cells in secondary tissue sites, including lymph nodes, gut, spleen, and the central nervous system, a successful HIV cure approach will almost certainly need to maintain function at these sites as well as in peripheral blood. However, decreased numbers and function of immune effectors like CAR T cells in tissues is a common limitation for solid tumors as well as HIV. Lessons from the cancer field highlight a key barrier to this goal—the immunosuppressive nature of the solid tumor microenvironment, which downregulates function and decreases persistence of CAR T cells (17–19) and other immunotherapies. Unsurprisingly, early studies similarly show only limited trafficking of virus-specific CAR T cells to sites of HIV-1 persistence, such as B cell follicles in lymph nodes, and a failure to recognize and clear infected cells at these sites (20–22).
Figure 1CAR T cell function above and below threshold levels of cognate antigen. Malignant cells, for example CD19+ leukemias, express high levels of CD19 antigen at the cell surface and are efficiently killed by CD19 CAR T cells (left). HIV-1–positive cells with latent infection express much lower levels of cell surface antigens (namely, Env), resulting in substantially lower killing efficiencies (middle). An approach to boost HIV-1 CAR T cells with cell-associated Env would provide exogenous antigen in vivo and increase CAR T killing efficiency (right).
The sparsity of cell-associated envelope (Env) antigen during ART-suppressed HIV-1 infection is also a critical barrier, juxtaposed with FDA-approved CAR T cell therapies for leukemia (Figure 1). CD19+ leukemias frequently contain kilogram quantities of malignant cells in peripheral blood and bone marrow and express high levels of surface CD19 that facilitate rapid and efficient recognition and killing by CD19 CAR T cells. In contrast, CAR T cell therapy for HIV is confounded by the extremely low expression of HIV-1 Env protein at the surface of latently infected cells, namely primary CD4+ T cells (23, 24) and by the low number of latently infected cells (no more than 1 per million CD4+ T cells) in a typical PLWH (13, 25). Several groups including ours have and continue to address these barriers in small and large animal models of HIV persistence (26, 27).
The clinical data from Liu et al. represent a welcome return of HIV-specific CAR T cells to the clinic. Iteratively developing gene therapy and gene editing approaches that augment CAR T cell safety, function, and persistence will be essential to further augment these therapies, with the ultimate goal of enabling lifelong HIV remission without the need for daily ART. Beyond optimizing the best CAR molecules and cell manufacturing approaches in preclinical models, aligning these studies with rationally designed clinical trials will, likewise, be critical. Our previous nonhuman primate study was designed to inform an ongoing clinical trial (Clinicaltrials.gov identifier NCT03617198), in particular focused on the timing between CAR T cell infusion and ATI. Liu et al. interrupted ART 3 to 6 weeks following infusion of CAR-modified cells, and it remains unclear whether a shorter period may be required to ensure remission (i.e., so that recrudescent viral antigen coincides with the peak window of CAR T cell immune surveillance in vivo). Other aspects, including exogenous antigen boosting, enhancement of cell-intrinsic CAR properties, and/or modifications to the local viral reservoir environment, may require further studies in preclinical models. The study by Liu et al. reminds us that CAR T cells were born as a treatment for infectious disease and, following lessons learned in cancer immunotherapy, have come full circle as an HIV-specific clinical therapy. Much work remains to develop this approach into a form that will consistently lead to HIV cure endpoints. A call to action to invest the necessary resources in this extremely promising immunotherapy, not just for HIV, but numerous other diseases, may provide profound clinical benefit.
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