CCR5 Analyses in HIV Infected Hematology Patients undergoing Umbilical Cord Blood Allogeneic Transplantation

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Patients with hematologic disorders who are HIV infected are generally excluded from allogeneic bone marrow/stem cell transplant (alloSCT) protocols. Anti-retroviral therapy (ART) is highly effective, safe, and convenient, however often patients maintain low circulating CD4 counts, and an increased pro-inflammatory state, with associated morbidity and mortality. AlloSCT for hematologic malignancies is curative in the majority of patients with otherwise lethal hematologic diseases via immune mediated effects termed graft vs. leukemia that reflect ultimate elimination of all transplant patient hematopoietic cells during establishment of full donor engraftment. This translational research program and clinical trial is designed to investigate whether the infusion of CCR5∆32 homozygous or heterozygous cord blood (CB) units, identified on unrelated CB registry search, may eliminate HIV infected recipient hematopoietic cells via allogeneic donor immunologic clearance of recipient hematopoietic cells in patients with hematological malignancies and HIV infection in need of an alloSCT. To reduce the risk of morbidity and mortality associated with prolonged cytopenia after cord blood transplantation, we will also use NLA101, which is a cryopreserved cell therapy composed of ex-vivo expanded CD34+ hematopoietic stem and progenitor cells originally isolated from umbilical CB units. Ten patients will be enrolled and treated at the following study sites: FHCRC (with its Cancer Consortium partners, University of Washington and Seattle Children’s Hospital), Case Western Reserve University – University Hospitals (Marcos de Lima, PI), Children’s Research Institute/Children’s National Medical Center (Blachy Davila-Saldana, PI), Memorial-Sloan Kettering Cancer Center (Juliet Barker, PI), and University of California- San Francisco (Timothy Henrich, PI). We will utilize the platform of alloSCT to gain further insights into potential clearance of HIV reservoir by allogeneic donor immune cell elimination of recipient hematopoietic cells, and examine immune reconstitution in these patients. We will use state of the art highly sensitive assays to monitor viral RNA and cell associated RNA and DNA to measure the decay of the HIV reservoir; an integrated immune monitoring approach that combines several high dimensional platforms (Transcriptomics, systems serology, multiparametric flow cytometry) will allow us to identify correlates and innate and adaptive immune mechanisms that are associated to control and decay of the HIV reservoir. This may allow HIV-1 infected patients to discontinue antiretroviral therapy (ART) for a sustained period without expected viral rebound, as has been observed over a 9 year time period in an HIV infected patient with leukemia treated with allogeneic stem cell transplant incorporating a CCR5∆32 homozygous graft (aka ‘Berlin patient’). It is expected that data acquired under this R34 over the next 36 months will inform the design and execution of a subsequent larger multi-site phase II study.