Research Highlights
Working across the boundary of the lab and clinic, program researchers are translating their discoveries into new therapies advancing the standard of care for patients with lymphoma and Hodgkin's disease worldwide. Below is a summary of their recent accomplishments:
- Dr. Felsher developed an animal model in which high grade lymphomas can be completely eliminated by turning off the expression of the MYC oncogene (PNAS 97: 10544, 2000; Nat Rev Cancer 3: 375, 2003; Blood 101: 2797, 2003;, Science 297: 102, 2002). This phenomenon of "oncogene addiction" has provided a tractable system for probing the genetic basis of malignancy and a rationale for the development of therapies targeted at the genetic program that originally resulted in the malignant phenotype.
- Dr. Shoshana Levy found that lymphoma cells in HCV infected patients and B cells from normal individuals making antibodies against HCV use the same set of V regions (Blood. 2001 Feb 15;97(4):1023-6). Her studies suggest that an immune response to the virus has gone awry (Leuk Lymphoma 44:1113, 2003). In support of the known epidemiologic association between lymphoma and hepatitis C virus, Dr. Shoshana Levy cloned and expressed B cell receptors from lymphomas in HCV-infected patients and found one lymphoma BCR was actually an antibody against the virus (Blood 98: 3745, 2001).
- Drs. Ronald Levy, Warnke, and Tibshirani co-authored together with Pat Brown (Program 5 Molecular Profiling) the seminal paper that described two major types of diffuse large cell B-cell lymphoma (DLBCL), germinal center B-cell and activated B-Cell, with markedly different survival outcomes (Nature 403: 503, 2000). Drs. R. Levy and Tibshirani used the DNA microarray data to discover a new gene, Hgal, whose expression correlated with survival in DLBCL (Nature 403: 503, 2003) and Drs. Natukunam, Tibshirani, Ronald and Shoshana Levy developed a new monoclonal antibody directed against Hgal (Blood 105: 3979, 2005).
- Drs. R. Levy and Tibshirani constructed a practical 6-gene model predictive of survival in DLBCL (N Engl J Med 350: 1828, 2004). Drs. Natkunam and Warnke analyzed protein expression in tissue microarrays constructed from 0.6 -1.5 mm cores from paraffin-embedded tumor samples, enabling the rapid survey of hundreds of patient samples in a single experiment (Mod Pathol 14: 686, 2001). The existence of TMAs that include over 750 lymphoma samples of various subtypes facilitates future study of novel antibodies directed against novel markers identified by gene expression profiling.
- Dr. Nolan has developed a novel technique for analysis of protein phosphorylation and cellular signaling events by multi-parameter flow cytometry (Clin Immunol 110: 206, 2004). This technique affords single cell profiling of potentiated phospho-protein networks in cancer cells, has demonstrated the potential for taxonomy of acute leukemia and is being studied in follicular lymphoma by Drs. Nolan and R. Levy (Cell 118: 217, 2004). Dr. Nolan has characterized the murine immunological signaling network with this technique that illustrates the principles by which immune regulation is context dependent and how in vitro culture systems compare with the in vivo environment (J Immunol 175: 2366, 2005).
- The pioneering efforts in therapeutic monoclonal antibodies by Dr. Ronald Levy led to development of the anti-CD20 antibody, rituximab, which has changed the treatment of lymphoma world-wide. Since our original report of activity in 1994 and the FDA approval of rituximab for recurrent indolent lymphoma in 1997, more than 500,000 patients have been treated. Drs. Weng and Ronald Levy found that inherited polymorphisms in the Fc receptors for Ig highly correlated with rituximab response, implicating a major role for antibody dependent cellular cytotoxicity in the mechanism of action of this drug (J Clin Oncol 21: 3940, 2003).
- Drs. Song and R. Levy described therapeutic vaccination against murine lymphoma by intra-tumoral injection of naïve dendritic cells (Cancer Res 65: 5958, 2005). This work is being translated into clinical studies in solid tumors and forms the basis for lymphoma clinical trials involving therapeutic vaccination with CpG oligonucleotides in B-cell lymphoma (Dr. R. Levy) and T-cell lymphoma (Dr. Kim).
- Stanford investigators were among the first to describe the therapeutic activity of rituximab in other lymphoroliferative disorders: lymphocyte predominant Hodgkin's disease by Dr. Horning (Blood 101: 4285, 2003), T-cell rich B-cell lymphoma by Drs. Natkunam and Horning (Clin Lymphoma 2: 185, 2001) and following bone marrow transplantation by Dr. Horning (Blood 103: 777, 2004). Highly influential phase III trials in diffuse large B-cell lymphoma (E4494) and indolent B-cell lymphoma (E1496) conducted by ECOG with Dr. Horning as senior investigator have contributed to the standard use of rituximab as primary therapy for these lymphomas.
- Drs. Horning, Hoppe , and Dr. Rosenberg have conducted a series of influential and successful prospective clinical trials in Hodgkin's disease that feature brief chemotherapy and involved field radiotherapy (J Clin Oncol 20: 630, 2002). The Stanford V regimen was successfully piloted in the ECOG and a phase III Intergroup trial (E2496) is nearing completion (J Clin Oncol 18: 972, 2000). Drs. Donaldson and Link led risk-adapted studies in pediatric Hodgkin's disease (Blood Rev 16: 111, 2002; J Clin Oncol 21: 2026, 2003) and are currently studying the Stanford V regimen in children. Many of the initial reports of late effects of Hodgkin's disease treatment following radiotherapy were described by Drs. Hancock and Hoppe (Eur J Haematol Suppl 66: 68, 2005, J Am Coll Cardiol 42: 743, 2003).
Trial Administration