Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS

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Abstract
Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer and show promise in treating HIV-1 infection. However, significant limitations are persistence and whether peripheral T cell-based products can respond to malignant or infected cells that may reappear months or years after treatment remains unclear. Hematopoietic Stem/Progenitor Cells (HSPCs) are capable of long-term engraftment and have the potential to overcome these limitations. Here, we report the use of a protective CD4 chimeric antigen receptor (C46CD4CAR) to redirect HSPC-derived T-cells against simian/human immunodeficiency virus (SHIV) infection in pigtail macaques. CAR-containing cells persisted for more than 2 years without any measurable toxicity and were capable of multilineage engraftment. Combination antiretroviral therapy (cART) treatment followed by cART withdrawal resulted in lower viral rebound in CAR animals relative to controls, and demonstrated an immune memory-like response. We found CAR-expressing cells in multiple lymphoid tissues, decreased tissue-associated SHIV RNA levels, and substantially higher CD4/CD8 ratios in the gut as compared to controls. These results show that HSPC-derived CAR T-cells are capable of long-term engraftment and immune surveillance. This study demonstrates for the first time the safety and feasibility of HSPC-based CAR therapy in a large animal preclinical model. Hematopoietic Stem/Progenitor Cell (HSPC) based gene therapy can be used to treat many infectious and genetic diseases. Here, we used an HSPC-based approach to redirect and enhance host immunity against HIV-1. We engineered HSPCs to carry chimeric antigen receptor (CAR) genes that detect and destroy HIV-infected cells. CAR therapy has shown huge potential in the treatment of cancer, but has only been applied in peripheral blood T-cells. HSPC-based CAR therapy has several benefits over T cell gene therapy, as it allows for normal T cell development, selection, and persistence of the engineered cells for the lifetime of the patient. We used a CAR molecule that hijacks the essential interaction between the virus and the cell surface molecule CD4 to redirect HSPC-derived T-cells against infected cells. We observed >2 years of stable production of CAR-expressing cells without any adverse events, and wide distribution of these cells in lymphoid tissues and gastrointestinal tract, which are major anatomic sites for HIV replication and persistence in suppressed patients. Most importantly, HSPC-derived CAR T-cells functionally responded to infected cells. This study demonstrates for the first time the safety and feasibility of HSPC based therapy utilizing an HIV-specific CAR for suppressed HIV infection.
Funding Information
  • amfAR, The Foundation for AIDS Research (108688-54-RGRL)
  • amfAR, The Foundation for AIDS Research (108929-56-RGRL)
  • California Institute for Regenerative Medicine (TR4-06845)
  • National Institute of Allergy and Infectious Diseases (1U19AI117941 – 01)
  • National Institute of Allergy and Infectious Diseases (1F32AI118565-01A1)
  • National Institutes of Health (AI060567)
  • National Institutes of Health (U19 HL129902)
  • National Institutes of Health (U19 AI0961110)
  • National Institutes of Health (R01 HL116217)
  • National Institutes of Health (R01 HL115128)

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