Clinical Trials of Patients with AIDS-Related Malignancies

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

This project is focused on the clinical study of patients with AIDS-related malignancies and related diseases. Much of the work is focused on tumors associated with Kaposis sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8). These tumors almost exclusively develop in HIV-infected patients, and the vast majority of our patients have HIV infection. This virus is the cause of Kaposi sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). We have recently completed a clinical trial of pomalidomide in KS, found it has substantial activity; we are continuing to analyze correlative data from this study. Based on this trial, it was given breakthrough drug designation by the US Food and Drug Administration and in May, 2020, it was given conditional approval for use in both HIV+ and HIV-negative Kaposi sarcoma. We have also initiated a follow-up trial to study the combination of pomalidomide and liposomal doxorubicin in patients with more severe KS. We are conducting a long-term clinical trial to study the natural history of KSHV-associated multicentric Castleman's disease (KSHV-MCD) and to explore various treatments. Some of the treatments include the combination of AZT and valganciclovir, a pro-drug of ganciclovir; liposomal doxorubicin and rituximab; and tocilizumab, a monoclonal antibody against the intrleukin-6 receptor. Results show that AZT plus valganciclovir has substantial activity, although relapses are common when used alone. We also have shown that the response rate and duration of response is higher wiuth rituximab plus liposomal doxorubicin. In a separate study, we have also shown that the IL-6-receptor antibody toclizumab has activity in KSHV-MCD. In addition, we are studying other patients with KSHV infection to assess factors that may be linked to malignancy. We have shown that the combination of methotrexate and rituximab is active in HIV-associated primary central nervous system lymphoma (PCNSL) and avoids the severe central nervous system toxicity found with radiation therapy. We have identified a group of patients with a new KSHV-related syndrome, called KSHV inflammatory cytokine syndrome (KICS), and opened a protocol to study this new disease. As part of this study, we are testing several possible therapies. We are collaborating with a number of other investigators to conduct translational studies related to HIV, AIDS-malignancies. In collaboration with the Cancer Immunotherapy Trials Network, we have initiated a phase I and feasibility trial of the anti-PD-1 inhibitor pembrolizumab in HIV-infected patients with a wide range of malignancies. Finally, based in part on our in vitro data showing that pomalidomide prevents KSHV-induced downregulation of MHC-1 and other immunologic surface markers, we have initiated a trial of lenalidomide, rituximab, and infusional chemotherapy for patients with primary effusion lymphoma and have initiated a trial of pomalidomide plus nivolumab in a variety of HIV-associated tumors and have initiated a study of the CDK4/6 inhibitor abemaciclib in patients with Kaposi sarcoma. We have also initiated a trial of NHS-IL12 as monotherapy and in combination with M7824 for Kaposi sarcoma and a trial in collaboration with the Cancer Immunotherapy Trials Network on the use of IL-7 in patients with KS. Finally, we are initiating a trial of pomalidomide, rituximab, and infusional EPOCH chemotherapy for HIV-associated B cell lymphomas.