cmv-specific hiv-car t cells as immunotherapy for hiv/aids

Conditions: HIV-1

Summary: human immunodeficiency virus type 1 (hiv-1) causes a persistent infection that ultimately leads to acquired immunodeficiency syndrome (aids). treatment of hiv-1 infection with combination anti-retroviral therapy (art) suppresses hiv-1 replication to undetectable viral levels and saves lives. nevertheless, art cannot eradicate latent cellular reservoirs of the virus, and hiv-1 infection remains a life-long battle. adoptive cellular immunotherapy using chimeric antigen receptor (car) engineered t cells directed against hiv-1 envelope subunit protein gp120 (hivcar t cells) may provide a safe and effective way to eliminate hiv-infected cells. however, the number of hiv-infected cells is low in participants under art, and car t cells disappear if they are not stimulated by their target antigens. interestingly, about 95% of hiv-1-infected individuals are cmv-seropositive and cmv-specific t cells have been shown to persist. to overcome the car t cells low persistence issue, we propose to make hiv-car t cells using autologous cytomegalovirus (cmv)-specific t cells, which can be stimulated by endogenous cmv in vivo. the overall hypothesis of this first-in-human phase 1, open-label, single-arm study is that endogenous immune signals to cmv-specific t cells can maintain the presence of autologous bispecific cmv/hiv-car t cells in healthy people living with hiv-1 (plwh), and achieve long-term remission in the presence of art.

human immunodeficiency virus type 1 (hiv-1) causes a persistent infection that ultimately leads to acquired immunodeficiency syndrome (aids). treatment of hiv-1 infection with combination anti-retroviral therapy (art) suppresses hiv-1 replication to undetectable viral levels and saves lives. nevertheless, art cannot eradicate latent cellular reservoirs of the virus, and hiv-1 infection remains a life-long battle. adoptive cellular immunotherapy using chimeric antigen receptor (car) engineered t cells directed against hiv-1 envelope subunit protein gp120 (hiv-car t cells) may provide a safe and effective way to eliminate hiv-infected cells. however, hiv-infected cells in participants under art, and car t cells disappear if they are not stimulated by their target antigens. interestingly, about 95% of individuals with hiv-1 are cmv-seropositive and cmv-specific t cells have been shown to persist at high frequency due to cmv antigen stimulation. to overcome the car t cells low persistence issue, we propose to make hiv-car t cells using autologous cytomegalovirus (cmv)-specific t cells, which can be stimulated by endogenous cmv in vivo. the overall hypothesis of this first-in-human, open-label, single-arm, pilot study is that endogenous immune signals to cmv-specific t cells can maintain the presence of autologous bispecific cmv/hiv-car t cells in healthy people living with hiv-1 (plwh). based on the results of this safety study, cmv vaccine and analytic treatment interruption will be evaluated with the cmv/hiv-car t cell investigational product in a subsequent protocol. the trial is a first-in-human, pilot study to evaluate the feasibility and safety and determine the maximum tolerated dose (mtd)/recommended phase ii dose (rp2d) of cmv/hiv-car t cells in plwh. eligible participants will temporarily interrupt their art regimen for 4 days prior to leukapheresis to prevent residual cell drug levels that could inhibit lentiviral transduction of the t cells during car t cell manufacturing. participants will resume their art regimen immediately after leukapheresis. if the manufacturing is not successful, a second apheresis may be scheduled no sooner than 3 weeks later with temporary interruption of art regimen for 4 days prior to leukapheresis. participants will resume their art regimen immediately after leukapheresis. once the final cell product is released, participants will receive a single intravenous (iv) infusion of autologous cmv/hiv-car t cells (defined as day 0). up to three doses of cmv/hiv-car t cells may be explored.

Eligibility criteria:
inclusion criteria: * participant must be ≥ 18 years of age at the time of screening; * karnofsky performance status (kps) ≥ 70; * documented hiv-1 infection anytime prior to study entry.; * on stable art with undetectable hiv-1 rna (i.e \< 20 copies /ml) for at least 48 weeks prior to screening (2 plasma hiv-1 rna blips 25-200 copies/ml are allowable); * cd4+ cell count ≥ 450 cells/μl; * adequate organ function; * willingness to interrupt art regimen for 4 days prior to leukapheresis; * not pregnant or breastfeeding. exclusion criteria: * concurrent illness or comorbid condition; * history of resistance to two or more classes of antiretroviral drugs; * history of prior receipt of an experimental hiv-1, immunotherapeutic agent, or gene therapy product.

Keywords: hiv-1, plwh (healthy people living with hiv-1) autologus cmv-specific t cells, anti-retroviral therapy (art), immunotherapy