ABOUT THE AIDS MALIGNANCY CONSORTIUM

The organization and structure of the AMC are designed to foster development of innovative research ideas designed to reduce the burden of malignancy among HIV-infected individuals. The AMC is composed of 5 Working Groups (WG), including 3 disease-based working groups, as well as a Laboratory Working Group and an International Working Group. These Working Groups are supported by the Group Chair's office, and the Operations, Data Management, and Statistical Centers to develop and oversee the scientific agenda, manage the group’s portfolio of clinical trials and correlative studies, and develop new protocols.

Kaposi’s Sarcoma Working Group

The leadership of the AMC KS Working Group collaborated with representatives of the NCI and the FDA to develop comprehensive, standardized evaluation procedures and data collection forms to capture KS response data in a manner that could be correlated with patient function (i.e., clinical benefit). These forms have been used in phase II and III AMC trials.

The current goals of the KS WG are to:

• Evaluate, in both domestic and international settings, the safety, toxicity and pharmacology of potential therapeutic and preventive agents that target factors or processes involved in the development and progression of Kaposi’s sarcoma (KS), and to determine whether such agents influence the clinical course and biology of the disease.
• Investigate diagnostic methods and prognostic factors associated with the development, clinical course and response to treatment of KS.

Lymphoma Working Group

The AMC has implemented and completed several seminal studies which have clearly changed the way in which patients with AIDS-related lymphoma (ARL) are treated, moving the field forward in a step-wise manner over the years, with the results of one study leading us toward the next hypotheses, studies and results. The modest effects of HAART on cyclophosphamide clearance suggested that careful monitoring should be incorporated into trials using higher doses of cyclophosphamide, as in the transplant setting. Nonetheless, the study showed that combination chemotherapy could be used safely with concomitant HAART.

The current goals of the Lymphoma WG are to:

• Determine the optimal treatment of patients with AIDS-related lymphoma and Hodgkin’s disease, within the context of highly active anti-retroviral therapy.
• Determine biologic correlates of disease and of response to therapy in patients with AIDS- related lymphoma and HD, in order to ascertain future targets for development and testing of innovative new therapies for affected patients.
• Determine any biologic or clinical differences between AIDS-related Burkitt’s lymphoma when diagnosed in the USA versus other regions of the world.

Human Papillomavirus Group

Human papillomavirus (HPV) is the most common sexually transmitted agent, infecting at least 75% of sexually active adults at some point in their lifetime. The importance of HPV lies in its etiologic association with squamous cell cancers of the epithelium, including the anus and cervix. The group evaluated new treatments for HPV-associated squamous cell cancers and pre-cancers associated with HPV, predominantly those arising in the anus and cervix, as well as, to perform correlative studies to better elucidate the pathogenesis of these diseases. Also, recognizing the rising incidence of HPV-associated anogenital cancers, the high prevalence and incidence of AIN 2-3 and the paucity of treatment options for either AIN or anal cancer. Similarly, although treatments for CIN such as loop electroexcision procedure (LEEP) have been proven to be safe and effective to prevent cervical cancer, these treatments sometimes fail, are expensive, are associated with morbidity and fail more often among HIV-positive women than HIV-negative women.

The current goals of the HPV WG are to:

• Evaluate the safety and efficacy of new methods of treatment and prevention of anal and cervical high-grade squamous intraepithelial lesion (HSIL) and anogenital cancer in HIV.
• Perform correlative scientific studies to elucidate the biology of anogenital HPV-related diseases in HIV-positive men and women, and to develop new molecular markers of prognostic value and ultimately therapeutic value.
• Train clinicians in high-resolution anoscopy to expand expertise and availability of this technique within the AMC.

Laboratory Working Group

The Laboratory Committee has provided histopathology review for all of the AMC lymphoma and KS studies to date. In addition, assessment of other well-standardized markers has been reviewed in the Laboratory Committee. This includes HIV load, CD4 T cell count, liver function tests, and immunoglobulin levels. The important findings in these regards have been summarized in the disease specific committees. AMC archival tissue (available through the AIDS and Cancer Specimen Bank) has been used to characterize the viral transcription profiles of lymphoma and KS. Real-time quantitative PCR techniques were applied to quantify all EBV and KSHV mRNAs. To date this represents the only transcriptional profiling performed on primary KSHV and EBV-associated tumors [as opposed to culture-adapted cell lines].

The impact of treatment with 5-azacitidine on EBV gene expression in AIDS lymphoma and other EBV-associated malignancies (AMC001) has been assessed using genomic sequencing and immunohistochemistry. The studies showed marked CpG demethylation immediately following treatment, but no substantial upregulation of viral antigen expression and no clinical responses.

The current responsibilities of the Laboratory WG are to:

• Monitor specimen acquisition and processing at AMC sites to assure proper and timely specimen collections
• Track and ship specimens to the AIDS and Cancer Specimen Resource (ASCR) or core laboratories.
• Assures that radiographic images are sent to the RTOG quality control center at University of Massachusetts for studies requiring outside radiology review.

International Working Group

The fundamental research focus of the East Africa – CWRU and the Brazilian collaborations in AIDS malignancies has been the pursuit of hypothesis-driven, pathogenesis-based, non-myelosuppressive therapeutic strategies. In 2002, the group published a review paper on AIDS lymphoma in the Journal of the National Cancer Institute. The major theme of the paper was to orient the research community to the therapeutic challenges of AIDS lymphoma in the resource-constrained setting. More recently, the group was invited to review the literature on AIDS-associated malignancies in developing nations.

The current goals of the International WG are to:

• Build capacity in developing nations for international AIDS-related cancer research aligned with the national AIDS research agenda with initial efforts focusing on emerging AMC international scientific collaborative partnerships in East Africa and Brazil.

• Develop AMC-sponsored and other joint NIH-supported international collaborative studies with our scientific partners with an emphasis on clinical trials that: 1) employ hypothesis-driven, pragmatic and non-myelosuppressive therapeutic interventions, 2) address important pathogenesis-based hypotheses in the resource-constrained setting; and 3) take advantage of unique scientific expertise available within the AMC and ACTG.

Capitalize on pragmatic clinical trial designs with laboratory correlative studies, which can serve as a conduit to obtain peripheral blood samples, paraffin-embedded tumor tissue, and cytological/fresh frozen tumor tissue from patients enrolled on the studies to be submitted to the NCI-sponsored AIDS and Cancer Specimen Resource (ACSR).

Representative Publications