Thalidomide and its analogues: implications for cancer therapy

Thalidomide and its immunomodulatory (IMiDs) analogs (lenalidomide, Revlimid, CC-5013; CC-4047, ACTIMID) are a novel class of compounds with numerous effects on the body's immune system, some of which are thought to mediate the anticancer and anti-inflammatory results observed in humans. Thalidomide is currently being used experimentally to treat various cancers and inflammatory diseases. It is approved for the treatment of dermal reaction from leprosy and is currently in phase III trials for multiple myeloma. Thalidomide and IMiDs inhibit the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukins (IL) 1beta, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). They also costimulate primary human T lymphocytes inducing their proliferation, cytokine production, and cytotoxic activity thereby increasing the T cells' anticancer activity. They induce an IL-2-mediated primary T cell proliferation with a concomitant increase in IFN-gamma production and decrease the density of TNF-alpha-induced cell surface adhesion molecules ICAM-1, VCAM-1, and E-selectin on human umbilical vein endothelial cells. Thalidomide stimulates the Th-1 response increasing IFN-gamma levels while CC-4047 increased IL-2 as well. Some of the above immunomodulatory activities along with anti-angiogenic, anti-proliferative, and pro-apoptotic properties are thought to mediate the IMiDs' antitumor responses observed in relapsed and refractory multiple myeloma and some solid tumor cancers. This has led to their use in various oncology clinical trials. The second generation IMiD, lenalidomide, has shown potential in treating the bone marrow disorders myelodysplastic syndrome and multiple myeloma. It is currently in phase II and III trials for these diseases respectively with numerous phase II trials in other hematologic and solid tumors.

PMID: 16146335 [PubMed - in process]

Superiority of Thalidomide vs VAD as primary Auto PBSC Therapy

Researchers from Italyrecently conducted a clinical trial to compare thalidomide to the chemotherapy regimen VAD (vincristine, doxorubicin, dexamethasone) in patients with newly diagnosed multiple myeloma. 200 patients received thalidomide or VAD prior to an autologous stem cell transplant. 76% of patients treated with thalidomide achieved an anti-myeloma response, compared with 52% of patients treated with VAD.

The researchers concluded that thalidomide appears superior to VAD as treatment prior to autologous stem cell infusion in patients with newly diagnosed multiple myeloma.
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(Abstract from "Blood" article follows)

The aim of the present study was to compare thalidomide-dexamethasone (Thal-Dex) and vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous peripheral blood stem cell (PBSC) transplantation for multiple myeloma (MM). For this purpose, we performed a retrospective matched case-control analysis of 200 patients who entered two consecutive studies from 1996 to 2004 and received Thal-Dex (n=100) or VAD (n=100) administered for 4 months before collection of PBSC and autologous transplantation. Matching criteria included age, clinical stage and serum beta2-microglobulin levels. In comparison with VAD, Thal-Dex resulted in a significantly higher response rate (52% versus 76%, respectively; P=0.0004) and effected more profound reduction in myeloma cell mass of both IgG (P=0.02) and IgA (P=0.03) type. More frequent toxicities included nonfatal deep vein thrombosis with Thal-Dex (15%) and granulocytopenia with VAD (12%). In each of the two treatment groups, 91% of patients proceeded to PBSC mobilization. The median number of collected CD34+ cells was 7.85 x 10⁶/kg in the Thal-Dex group and 10.5 x 10⁶/kg in the control group. Thal-Dex may be considered an effective and relatively well tolerated oral alternative to the more complex VAD regimen as front-line therapy for MM patients who are candidates to subsequent autologous transplantation.

Michele Cavo^*, Elena Zamagni, Patrizia Tosi, Paola Tacchetti, Claudia Cellini, Delia Cangini, Antonio de Vivo, Nicoletta Testoni, Chiara Nicci, Carolina Terragna, Tiziana Grafone, Giulia Perrone, Michela Ceccolini, Sante Tura, and Michele Baccarani

Institute of Hematology and Medical Oncology 'Seragnoli', University of Bologna, Bologna, Italy

Blood First Edition Paper, prepublished online March 10, 2005; DOI 10.1182/blood-2005-02-0522

Advances in Myeloma Genetics and Prospects for Pharmacogenomic Testing

Pharmacogenomic studies in multiple myeloma, a neoplasia of clonally expanded malignant bone marrow plasma cells, are helping to set the stage for individualized therapy. Although relatively few in numbers, these studies are already providing new therapeutic targets and avenues for drug discoveries as well as contributing to novel prognostic markers in multiple myeloma. High-throughput mutation screening of the kinome promises to identify further novel targets for therapy. Genetics and gene expression profiling technology have improved molecular-based patient stratification and prognostic staging, expanded knowledge of the molecular mechanism of chemotherapeutic agents, and provided a better understanding of myeloma bone disease. The use of pharmacogenomic strategies in myeloma is thus already changing medical practice.

Claudio, Jaime O.; Stewart, A. Keith, Department of Medical Oncology, Princess Margaret Hospital, Toronto, and McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Ontario, Canada

American Journal of PharmacoGenomics, 2005, vol. 5, no. 1, pp. 35-43(9)

John Hopkins - Myeloma Vaccine Update

In efforts to educate the body to fight off cancer, researchers have found that some immune cells are "smarter" than others. Working with collections of human cells, Johns Hopkins Kimmel Cancer Center scientists tested kill-rates of two kinds of T-cells "primed" to home in on myeloma. Those that live in the bone marrow outperformed their counterparts circulating in the blood by more than 90 percent.

"It is very difficult to design cancer therapies that get the body's immune system to recognize and kill cancer cells that the system has ignored for a long time," says Ivan Borrello, M.D., assistant professor of oncology and director of the research, which is published in the March 1 issue of Cancer Research. "Now, we have evidence that 'educating' T-cells in the bone marrow may be the most effective way to get an anti-tumor response."

T-cells are responsible for identifying cells that are foreign to the body, including genetically altered cancer cells, and marking them for destruction. In the Hopkins study of both kinds of T-cells, those from the blood and bone marrow, scientists mixed them with magnetic beads coated with tumor antibodies, a sort of "artificial intelligence" that activated and expanded the T-cells' cancer-killing mode.

The marrow T-cells identified not only mature myeloma cells but the primitive cells responsible for the disease. Activated bone marrow T-cells stopped the growth of 86 percent of myeloma stem cell colonies compared to 47 percent for activated t-cells taken from circulating blood. The researchers' next step is to determine whether the cells' ability to limit cancer growth in culture dishes ultimately may do the same in patients.