Jodi B. Black, Ph.D., Program Director

The AIDS Malignancy Program (AMP) contributes to the NCI discovery, development, and delivery mission by supporting preclinical and clinical studies of cancer treatment in HIV-positive and immunocompromised patients. The AMP also supports resources for preclinical and translational/interdisciplinary studies, including a tissue repository of well-characterized specimens collected from HIV-positive and -negative patients, infrastructure at institutions that receive significant AIDS funding, and capacity building for basic and clinical research in resource-poor countries with significant HIV/AIDS prevalence.

GRANTS

Access to Biospecimens
The AIDS and Cancer Specimen Resource (ACSR), formerly known as the AIDS and Cancer Specimen Bank, successfully recompeted for five years of funding. The ACSR expanded its existing specimen program with a broadened scope of collection, new technologies, and a new central coordinating office at the University of California-San Francisco, which manages central database functions, application processing, and outreach activities. The office will also address human subject research issues relevant to its services. Other ACSR sites include George Washington University, Ohio State University (OSU), and more than 20 national and international collaborative sites. Formal collaborations were established with investigators conducting relevant research in Thailand, Uganda, Kenya, and Zimbabwe. The name change follows a strategic reconfiguration of operations and more accurately reflects the expansion of ACSR services to researchers. The ACSR is the country's leading nationwide multisite collection program that includes a bank of specimens for investigators in such fields as HIV/AIDS and related cancer and virology. The ACSR will also act as an advocate for researchers by seeking out, on their behalf, materials not in ACSR possession.

The AMP funded the first AIDS oncology integrated basic, preclinical, and clinical research program project grant, Innate Immunity: Elucidation and Modulation for Cancer Therapy, at the OSU Comprehensive Cancer Center. The project, composed of four projects and four cores, will study the mechanisms and biology of key cells and molecules of the innate immune system. The central hypothesis is that modulating these cells can significantly affect the efficacy of biologic therapy for cancer prevention and treatment of hematologic malignancies in HIV-positive and -negative patients.

Study of New Drug for AIDS-Associated Kaposi's Sarcoma
In 2001 the AMC completed its first phase III trial, which was designed to compare response rates of IM862 and placebo for patients with AIDS-associated Kaposi's sarcoma (AIDS-KS). IM862 is a synthetic dipeptide with in vitro and in vivo anti-angiogenic properties. Based on prior phase I and II data that confirmed the lack of toxicity and suggested a response rate of 36% in AIDS-KS, a randomized, placebo-controlled phase III trial was initiated with the phase II dose, 5 mg intranasally every other day. Two hundred and two patients were enrolled, 104 on IM862 and 98 on placebo. All patients were included in the intent-to-treat analyses and only one did not receive the study drug. About 50% of patients received prior local therapy for KS. Prior systemic non-investigational therapy was reported by 62%, most commonly Doxil^®, paclitaxel, and DaunoXome^®. Sixty-three percent of patients in the IM862 group were receiving prior, stable regimens of highly active antiretroviral therapy (HAART) with protease inhibitors, as were 69% in the placebo group. Median treatment durations were 19.5 weeks (IM862) and 24 weeks (placebo). No significant difference was detected between the groups with respect to response rate (21-24%), time to response, or response duration. Median time to progression was 20 weeks on IM862 and more than 30 weeks on placebo. Grade 3 or 4 toxicities were reported in 17 IM862 and 20 placebo patients. Two IM862 and three placebo patients experienced grade 3 or 4 adverse events reported as possibly, probably, or definitely related to study drug. Despite successful phase I and phase II studies, the IM862 phase III study failed to provide evidence for efficacy and may accelerate time to progression. There is a significant response rate to ongoing HAART alone.

CHOP Chemotherapy Trial for HIV-associated Non-Hodgkin's Lymphoma Patients
To determine whether adding rituximab to CHOP (a chemotherapy regimen of cyclophosphamide, doxorubicin/hydroxydoxorubicin, vincristine [Oncovin^®], and prednisone) results in a higher response rate, patients with HIV-associated aggressive B-cell lymphoma were randomized to receive standard-dose CHOP with rituximab (group A, 95 patients) or CHOP alone (group B, 47 patients). All received cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², vincristine 1.2 mg/m², and prednisone 100 mg a day for five days. Those in group A received rituximab d1 and CHOP d3 of each cycle. Three monthly maintenance doses of rituximab were administered in group A after completion of chemotherapy. All patients received granulocyte colony stimulating factor support beginning in cycle 1. Patients were restaged every two cycles. Mean age was 42 (26-73). Median CD4+ lymphocyte count was 133/mm³. Serum lactate dehydrogenase was 351, and 79% had stage III or IV disease. There were no significant differences in these baseline characteristics between the two study arms.

Complete response was achieved in 58% (group A) and 50% (group B) of patients, with median times to response of 8.5 (group A) and 9 weeks (group B). With a median of 26 weeks of follow up, neither group reached median response duration. Grade 3/4 neutropenia was reported in 39% of group A and 17% of group B patients. Death due to infection occurred in seven group A patients and one in group B. Overall, fever with an absolute neutrophil count of less than 1000/mm³ occurred in 25% of group A and 8.5% of group B patients. Documented infection in the setting of neutropenia occurred in 10 (group A) and zero group B patients.

Preliminary results of this trial indicate no benefit to adding rituximab to CHOP for initial treatment of HIV-associated non-Hodgkin's lymphoma patients, and the high incidence of neutropenic infection and death in those receiving rituximab raises serious concerns about the safety of this approach.

Phase I Trial of Col-3 in Patients with HIV-Related Kaposi's Sarcoma
The objectives were to determine the safety and toxicity of oral Col-3, a matrix metalloproteinase inhibitor (MMP), in patients with HIV-related Kaposi's sarcoma (HIV-KS); evaluate the effects on HIV viral load and immune parameters; characterize the pharmacokinetics; and evaluate the impact on angiogenesis. Eighteen patients received Col-3 in dosing cohorts of 25, 50, and 70 mg/m²/day. The overall response rate was 44%, with a median response duration of 25 or more weeks. Of 18 patients, seven reported drug-related grade 3 or 4 adverse events, primarily photosensitivity. The median half-life of Col-3 in this study was 39.3 hours. Results indicated that Col-3 administered orally once a day to patients with HIV-KS is reasonably well tolerated. The most common reported adverse events were photosensitivity and rash. Antitumor activity observed in the phase I study was the basis for developing the phase II Col-3 trial for HIV-KS. An open-label, randomized two-arm study was designed to evaluate tumor response rate and response duration of treatment with Col-3 at 50 mg/day versus 100 mg/day, biologic activity of the agent by measuring percent apoptotic cells on tumor biopsies pre- and posttreatment, and the effect of Col-3 on serum MMP-2 and MMP-9 levels. Analysis is ongoing.

Investigator-Initiated Translational Research
Several investigators are working on viral-targeted therapies for AIDS malignancies translated basic bench research to novel therapy. Dr. Michael Caligiuri developed a reproducible preclinical model of Epstein-Barr virus-positive (EBV+) primary central nervous system lymphoma (PCNSL) in the nude rat. The safety and efficacy of radiation and antiviral agents for inducing tumor cell apoptosis was assessed in this model. A combination of zidovudine (AZT) plus ganciclovir (GCV) plus low-dose external beam radiation therapy (XRT), previously shown to induce apoptosis of an EBV+ cell line, extended rat survival time when compared to the antivirals or XRT alone. Upregulation of EBV thymidine kinase (TK) was detected after exposure to XRT in the triple regime. The novel observation that XRT induces viral TK, which further sensitized tumors to AZT and GCV, led to the development of a phase I clinical trial. A renal transplant recipient with aggressive EBV+ PCNSL who was unresponsive to immunosuppressive taper achieved a complete response after treatment with this regime and is disease free after three years [1].

Dr. Shannon Kenny showed that GCV enhances tumor cell killing induced by chemotherapy and irradiation. Because both are known to induce the lytic form of EBV replication and only a small percentage of tumor cells are infected with the virus, she developed a model for this synergistic effect. Induction of EBV lytic replication by XRT or chemotherapy results in GCV phosphorylation to its active form by the EBV lytic gene TK. The active form of GVC can then be transferred to adjacent tumor cells and kill them. This novel hypothesis led to the development of phase I/II trials to determine whether the combination of conventional irradiation and GCV is more efficacious (or toxic) than irradiation alone for treating AIDS-related PCNSL.

Investigations into the mechanisms of cell death induced by AZT and interferon-alpha (IFN-alpha) in EBV+ lymphomas and human herpes virus-8-positive (HHV-8+) primary effusion lymphomas (PEL) indicated that there were two distinct pro-apoptotic effects of these agents in primary lymphoma cell lines derived from AIDS patients. EBV+ Burkitt's lymphoma (BL) cell lines underwent apoptosis in the presence of AZT alone, but HHV-8+ PEL cell lines required the addition of IFN-alpha. Investigation into the mechanisms of IFN-alpha-induced apoptosis indicated that IFN-alpha induces the soluble death-receptor ligand TRAIL, which, when combined with AZT, blocks expression of the anti-apoptotic NFkappaB, resulting in initiation of a suicide program in these HHV-8 infected lymphomas. In contrast, IFN-alpha did not increase the apoptotic effect of AZT in EBV+ BL. This novel, targeted therapeutic approach was used to treat an HIV+ PEL patient, and led to complete resolution of the malignant effusion in five days [2,3].

References 1. Roychowdhury S, Peng R, Baiocchi RA, et al. Experimental treatment of Epstein-Barr-virus-associated primary central nervous system lymphoma. Cancer Research 2003;63:965-71. 2. Toomey NL, Deyev VV, Wood C, et al. Induction of a TRAIL mediated suicide program by interferon alpha in primary effusion lymphoma. Oncogene 2001;20:7029-40. 3. Ghosh SK, Wood C, Boise LH, et al. Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidine-mediated inhibition of NF-kappaB. Blood 2003;101:2321-7.

International Efforts
The AMP funded the first multicenter clinical trial in Africa to treat AIDS-related non-Hodgkin's lymphoma (NHL) using an oral-based combination chemotherapeutic regime. Dr. Scot Remick of Case Western Reserve University (CWRU) and African colleagues Dr. Edward Mbidde (Uganda) and Dr. Otieno Mwanda (Kenya) are conducting this multicenter trial. Patient accrual is expected to be completed in three years.

The AMP partners with the Fogarty International Center (FIC) on the AIDS International Training and Research Program (AITRP). The AITRP supports HIV/AIDS international training and research for foreign health scientists, clinicians, and allied health workers from developing countries and emerging democracies. The goal is to build biomedical and behavioral research capacity for preventing HIV/AIDS. Rates of HIV-associated malignancies have increased in developing countries as a result of the HIV epidemic, and the AMP is helping strengthen the capacity for such research. Investigators from the Johns Hopkins University, the University of Washington, CWRU, and the University of California-Los Angeles, received supplements for research involving Kaposi's sarcoma (KS), non-Hodgkin's lymphoma, and human papillomavirus-related anogenital disease in India, Uganda, Brazil, Kenya, Malawi, and Thailand as follows:

Foster the development of a Center for Excellence in human herpes virus-8/KS herpes virus (KSHV) research in Kenya.

Build capacity for research and clinical trials involving HIV-associated malignancies (KS and AIDS-related lymphomas) for health care professionals in Uganda.

Train investigators in Uganda to diagnose, treat, and prevent cervical cancer.

Train investigators in India to detect, treat, and prevent cervical carcinoma, and evaluate the effects of HIV on human papillomavirus (HPV) acquisition, persistence, and risk for cervical carcinoma.

Provide research-training opportunities in AIDS-associated malignancies to investigators to enhance their ability to conduct research in Brazil.

The AMP is partnering with FIC on the International Clinical, Operational, and Health Services Research Training Award for AIDS and Tuberculosis (ICHORTA-AIDS/TB) program. The program fosters collaborative, multidisciplinary research in developing countries where AIDS, TB, or both are significant problems. The first phase consists of one-year planning grants to the foreign site to organize, plan for, prepare, and assemble an application for a comprehensive ICHORTA cooperative agreement (phase II). Partnering with a domestic institution with recognized HIV expertise is required. The goal is to build capacity for integrated clinical operations and health services research encompassing the range of AIDS-related conditions and issues, including malignancy. The following proposals chosen for co-funding were relevant to current program studies and interests, and to establish geographic diversity in areas with endemic virus-associated malignancies:

Investigators from the Federal University of Bahia will partner with collaborators at Cornell University, the University of Miami, and the University of Nebraska to develop a phase II application with emphasis on viral-related malignancies in the context of HIV in Bahia, Brazil. U.S. collaborating investigators are funded by NCI to conduct epidemiologic, basic, and clinical research in viral malignancies in the context of HIV infection. ICOHRTA participation will build another bridge between the foreign and U.S. site for research and treatment studies on malignancies associated with endemic viruses in an area with high HIV prevalence.

Investigators from the University of Natal will develop a phase II application with investigators at Columbia University. The AMC wants to expand into this region and is funded to conduct a clinical trial feasibility study and a study to measure the cellular immune response to human herpes virus-8 as part of a mother-to-child transmission study in South Africa. AMC investigators have proposed conducting a trial in this region using highly active antiretroviral therapy as a treatment for KS, where 80% of KS patients are HIV+. Other clinical trials capacity building at the University of Natal, Durban, will facilitate future interactions with NCI cooperative groups.

Investigators involved with the Joint Clinical Research Center (JCRC), Kampala, Uganda, will collaborate with investigators at CWRU. Results of a successful phase II application will build a bridge between JCRC and CWRU for ongoing clinical studies, facilitate the ACSR tissue-banking endeavor, and facilitate NCI expansion into this region.

Investigators from the Instituto de Medicin Tropical, Lima, Peru, propose to develop a comprehensive phase II application with investigators at the University of Alabama. An aim is a systematic evaluation to determine the extent of HIV seroprevalence in Lima, with emphasis on co-infection with the endemic human T-cell leukemia virus type 1 (HTLV-1). The unique problem of HTLV-1 co-infection and development of adult T-cell leukemia/lymphoma is an important factor to study relevant to HIV.

Investigators from the All India Institute of Medical Services (AIIMS), New Delhi, plan to develop a phase II application in collaboration with investigators at the University of California, Los Angeles. The AIIMS is a well-established institution with extensive clinical facilities. HPV-associated cervical cancer is the leading cause of cancer death in women in this region, and 3.8 million HIV-infected persons live in India.

TARGETED INITIATIVES

To enhance NCI's contribution to understanding the interplay between HIV/AIDS and the development and control of comorbid conditions and malignancies, the AMP, in collaboration with the Division of Cancer Biology and the Division of Cancer Control and Population Sciences (DCCPS), developed a concept request for supplemental applications for NCI-funded investigators to bridge research in viral oncology, cancer biology, and preclinical and clinical studies relevant to cancer in HIV/AIDS or acquired immunodeficiencies. The concept was approved and released for FY 2003 funding using DCTD-controlled funds.

The AMP collaborated with the following Institutes and Centers to reissue Program Announcements:

DCCPS, NCI: Molecular epidemiology of cancers associated with acquired Immunodeficiency

FIC: AITRP and ICHORTA

DAIDS, NIAID: Centers for AIDS Research

WORKSHOPS/MEETINGS

Since 1997, the NCI has presented an annual international conference on malignancies in AIDS and other immunodeficiencies to showcase progress and stimulate research in diverse disciplines. In 2002, the AMP sponsored the 6th International Conference for Malignancies in AIDS and Other Immunodeficiencies: Basic, Epidemiologic and Clinical Research. Continuing Medical Education-accredited meeting summaries were published online at Medscape http://www.medscape.com/.