CAR-INKT IMMUNOTHERAPY CELLS AS A HIV CURE INTERVENTION
The key barrier to HIV eradication is the presence of latently infected T cells within blood and tissue sites which act as a source of viral rebound on cessation of antiretroviral therapy and as a sanctuary for ongoing viral replication on ART. Innovative approaches to deplete the HIV reservoir are needed in addition to ART to reach a state of viral control off ART; or viral remission.
Chimeric Antigen Receptor (CAR) engineered T cells have been used successfully to treat lymphoma. However these cells a complex bespoke process which requires an allogenic transplant and engineering of T cells to circumvent the possibility of graft versus host disease. CAR-based therapy that employs a different kind of T cell, namely an invariant natural killer T cell (iNKT) offer the advantage that they don’t need to be harvested from the same patients in which they’re going to be used (i.e. they can be produced off the shelf); they can be taken from any healthy individual. For this reason, therapies based on iNKT cells hold the potential for easy and cheap mass production. One potential novel approach in HIV cure is the use of highly sensitive, HIV-specific genetically manipulated CAR-iNKT-cells. Research developing chimeric antigen receptor invariant natural killer T cells (CAR-iNKT) to target HIV is currently underway at Imperial College is led by Prof Karadimitris’s group at the Hammersmith campus in collaboration with Dr John Thornhill and Professor Fidler. Dr Thornhill is leading work to investigate if this technology is feasible in people living with HIV by assessing if these novel CAR-iNKT cells can access anatomical HIV reservoirs such as the gut and if these engineered CAR-iNKT have the potential to target HIV proteins and eliminate HIV infected cells.
Thornhill JP, Pace M, Martin GE, Hoare J, Peake S, Herrera C, Phetsouphanh C, Meyerowitz J, Hopkins E, Brown H, Dunn P, Olejniczak N, Willberg C, Klenerman P, Goldin R, Fox J, Fidler S, Frater J; CHERUB investigators. CD32 expressing doublets in HIV-infected gut-associated lymphoid tissue are associated with a T follicular helper cell phenotype. Mucosal Immunol. 2019 Sep;12(5):1212-1219. doi: 10.1038/s41385-019-0180-2. Epub 2019 Jun 25. PMID: 31239514.
Thornhill JP, Lynch KD, Skelton JK, Dorner M, Khan M, Martin GE, Hoare J, Peake S, Frater J, Fidler S. Vedolizumab use and the associations between α4β7 expression and HIV reservoir in the gut during treated primary HIV infection. AIDS. 2019 Nov 15;33(14):2268-2271. doi: 10.1097/QAD.0000000000002344. PMID: 31688047.
Thornhill J, Fidler S, Frater J. Advancing the HIV cure agenda: the next 5 years. Curr Opin Infect Dis. 2015 Feb;28(1):1-9. doi: 10.1097/QCO.0000000000000123. PMID: 25485650.
Gupta RK, Peppa D, Hill AL, Gálvez C, Salgado M, Pace M, McCoy LE, Griffith SA, Thornhill J, Alrubayyi A, Huyveneers LEP, Nastouli E, Grant P, Edwards SG, Innes AJ, Frater J, Nijhuis M, Wensing AMJ, Martinez-Picado J, Olavarria E. Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report. Lancet HIV. 2020 May;7(5):e340-e347. doi: 10.1016/S2352-3018(20)30069-2. Epub 2020 Mar 10. PMID: 32169158.