CLINICIANS/ SCIENTISTS

LYMPHOMA FOUNDATION GRANTS HAVE BEEN RECEIVED BY:
Members of the Memorial Sloan Kettering Cancer Center (MSKCC) representing many departments and services: AND other Major Cancer Centers

Kenneth Offit, MD, MPH  
Dr. Kenneth Offit  is the Director of the Clinical Genetics Service at the Memorial Sloan Kettering Cancer Center and author of Clinical Cancer Genetics 
 

Is there a genetic (inherited) component that protects against the development of cancer? "As a result of the “genetic revolution” it is now possible to look for genetic variations between individuals and to learn if these are associated with disease.  The goal of one aspect of our genetic research  at the Memorial Sloan Kettering Cancer Center has been to use “whole genome” technologies to look for genetic markers that will predict resistance to disease in the elderly.  Our initial research paper soon to be published demonstrated that it is possible to do “whole genome” analysis to “rediscover” known genes.  As preliminary data we performed low density genomic scans and we have been able to resolve two significant regions: one on chromosome 12 and one on chromosome 22 that may be associated with the resistance to breast cancer in this elderly population.  As we continue our research we hope to better map these regions and to discover other genetic regions that confer cancer resistance in the elderly." Kenneth Offit, M.D.MPH

See published research in 2002-2006  by Dr. Offit and colleagues supported in part by Lymphoma Foundation grants
 

 LYMPHOMA/MYELOMA SERVICE - WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY - John P. Leonard, M.D.

Monoclonal antibody, Anti-sense BCL-2 and Bortezomib therapy (2005-2006) “The assistance of the Lymphoma Foundation [will] be used to support the following efforts at our center in very meaningful ways…”

“Novel initial therapies for aggressive lymphoma.  We continue to explore ways to improve outcomes with chemotherapy, particularly combinations of CHOP chemotherapy and rituximab along with agents such as Bcl-2 antisense, idiotype vaccines, and bortezomib (Velcade).  Trials with these are ongoing, and initial phase I results of the CHOP-R-Velcade study have been submitted to ASH.  We are excited about these preliminary findings, and the support from the Lymphoma Foundation will help us to continue this trial as well as to conduct correlative studies on tumor tissue that will allow us to characterize tumors from the molecular standpoint in the patients on the study.  We also plan additional future trials with other novel agents.”

“Further assessment of the anti-CD22 antibody epratuzumab and other antibodies in B-cell malignancies.  We continue to study this agent, with which we have demonstrated evidence of clinical activity and manageable toxicity.  We are evaluating patients treated with single-agent epratuzumab, repeated courses (at relapse) as well as in combination with rituximab.  Substantial numbers of these patients remain in remission years later (initial results from one study recently reported in JCO).  Our initial efforts are encouraging in this regard, and we are currently conducting a pilot study in lymphoplasmacytic lymphoma (which highly expresses CD22).  We are also attempting to identify clinical, laboratory, and pathologic parameters, which may correlate with response and therefore allow us to better target appropriate patient populations.  Further trials in combination with CHOP-R and with rituximab are being planned.  Additionally, we are currently conducting phase I studies with anti-CD40 and anti-interleukin 6 monoclonal antibodies.”

Dr. John P. Leonard  is the Chief of the Lymphoma/Myeloma Service, Division of Hematology  and Oncology , Weill Medical College of Cornell University, New York Presbyterian Hospital, New York Weill Cornell Center

IN 2004-2006 THE LYMPHOMA FOUNDATION INCREASED ITS COMMITMENT TO RESEARCH DIRECTED TOWARD THE IMPROVING THE CARE AND TREATMENT OF CHILDREN WITH CANCER

WITH SPECIAL ADDITIONAL GRANT SUPPORT RECEIVED FROM THE JOSEPH LeROY and ANN C. WARNER FUND THE FOLLOWING RESEARCH WAS ACHIEVED AND PUBLISHED  BY RESEARCH TEAMS OF DR. DAVID SCHEINBERG, DR. KENNETH OFFIT AND DR. JOACHIM YAHALOM
2006
Cancer Genetic Testing and Assisted Reproduction by Offit K, Kohut K, Clagett B, Wadsworth E, Cummings S, White M, Sagi M, Bernstein D, Davis JG. was electronically published online by the Journal of Clinical Oncology in July, 2006 and was formally published in October 2006
2005
Targeted deletion of T-cell clones using alpha-emitting suicide MHC tetramers Rui Rong Yuan, Phillip Wong, Michael R. McDevitt, Ekaterina Doubrovina, Ingrid Leiner, William Bornmann, Richard O’Reilly, Eric G. Pamer, and David A. Scheinberg  Blood. 2004;104:2397-2402 Molecular Pharmacology and Chemistry Program; Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York Efforts to Control the Errant Products of a Targeted In vivo Generator Jaspreet Singh Jaggi, Barry J. Kappel, Michael R. McDevitt, George Sgouros, Carlos D. Flombaum, Catalina Cabassa, and David A. Scheinberg  Molecular Pharmacology and Chemistry Program; Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; and Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland  Cancer Res 2005; 65: (11). June 1, 2005

The TP53 mutational spectrum and frequency of CHEK2*1100delC in Li-Fraumeni-like kindreds Rina Siddiqui, Kenan Onel, Flavia Facio, Kedoudja Nafa, Louis Robles Diaz, Noah Kauff, Helen Huang, Mark Robson, Nathan Ellis and Kenneth Offit  Memorial Sloan Kettering Cancer Center, Clinical Genetics Service, Department of Medicine, New York, USA; Hospital Universitario Doce de Octubre, Madrid, Spain; Department of Pediatrics, University of Chicago, Chicago, Illinois, USA   Familial Cancer (2005) 4: 177-181

Intensity-modulated radiotherapy for lymphoma involving the mediastinum  Karyn A. Goodman M.D., Sean Toner M.S., Margie Hunt M.S., Elisa J. Wu M.D. and Joachim Yahalom M.D. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY  Online 22 April 2005. Int J Radiat Oncol Biol Phys. 2005 May 1;62(1):198-206.  Radiation Treatment Planning Techniques for Lymphoma of the Stomach Cesar Della Biancia, M.S., Margie Hunt, M.S., Eli Fuhrang, Ph.D., Elisa Wu, M.D., and Joachim Yahalom, M.D. Departments of  Medical Physics and Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY   Int. J. Radiation Oncology Biol. Phys. in press 2005
 

The research team headed by David Scheinberg, MD, PhD of the Memorial Sloan Kettering Cancer Center continues to make progress in their work in the field of targeted alpha-particle therapy and atomic nanogenerators. Significance: The focus of this extended research is on the development of these novel structures that target the leukemias which are the most common form of hematologic cancers in children.

The genetic research group headed by Kenneth Offit, MD, MPH of the Memorial Sloan Kettering Cancer Center (MSKCC) analyzed families with the Li Fraumeni syndrome and cancer predisposition in children. Significance: The genetic description of Li Fraumeni syndrome allows  parents of children affected with cancers a better understanding of the causes of the cancers in their family as well as a potential means to better define the risks for occurrence of cancers in other children. 

The radiation oncology research group headed by Joachim Yahalom, MD of the Memorial Sloan Kettering Cancer Center (MSKCC) is continuing to develop and apply Intensity Modulated Radiation Therapy (IMRT) for young children, teenagers and young women receiving treatment for Hodgkin’s disease. Significance: The reduction of breast exposure to radiation in children, adolescents and young women treated for Hodgkin lymphoma will minimize or eliminate the long-term increased risk of radiation-induced secondary breast cancer that occurs after upper body irradiation.

DEVELOPING A VACCINE AGAINST CANCER

DEVELOPING A VACCINE AGAINST LYMPHOMA: THE WHEELS OF SCIENTIFIC RESEARCH ADVANCE SLOWLY and DEPEND ON THE INTELLECT, INNOVATION, INTEGRITY AND PERSISTENCE OF THE RESEARCHERS and THE SUPPORT THEY RECEIVE TO CONTINUE THEIR WORK OVER MANY YEARS BEFORE ANY DEFINITIVE RESULTS ARE ACHIEVED. The Lymphoma Foundation has maintained its grant support toward the development of a cancer vaccine over many years. The diligent application of innovative concepts and the practical application of basic laboratory research by Dr. Houghton and his research team has resulted in the latest advance as noted in Dr. Houghton's notes to the Lymphoma Foundation in July 2007:

In the PROGRESS REPORT FOR THE LYMPHOMA FOUNDATION submitted by Maria Lia Palomba, MD and Alan N. Houghton, MD they noted further progress leading toward a cancer vaccine clinical trial:  PART I: “We have constructed a set of CD20 vectors with predicted enhanced immunogenicity based on either the creation of novel MHC high-affinity epitopes by site directed mutagenesis or by fusing the CD20 DNA (naïve, xenogeneic or epitope­optimized) with fusion partners which our laboratory has shown to improve DNA vaccines efficacy. We have shown that single amino acid mutations at anchor residues of MHC class I epitopes can increase their affinity for the cognate MHC molecule (1). Using an algorithm generated in our laboratory, with support of the Lymphoma Foundation (2), we have identified several potential heteroclitic epitopes, both in the extracellular portion of CD20 and across the entire span of the CD20 protein.

(1) Guevara-Patino, J.A., M.E. Engelhorn, M.J. Turk, C. Liu, F. Duan, G. Rizzuto, A.D. Cohen, T. Merghoub, J.D. Wolchok, and A.N. Houghton. 2006. Optimization of a self antigen for presentation of multiple epitopes in cancer immunity. J Clin Invest 116:1382-1390.   (2) Houghton, C.S., M.E. Engelhorn, C. Liu, D. Song, P. Gregor, P.O. Livingston, F. Orlandi, J.D. Wolchok, J. McCracken, A.N. Houghton, and J.A. Guevara-Patino. 2007. Immunological validation of the EpitOptimizer program for streamlined design of heteroclitic epitopes. Vaccine, in press.”

PART II: JULY 2007 TO THE LYMPHOMA FOUNDATION: BY Maria Lia Palomba, MD and Alan N. Houghton, MD:  Regarding a clinical trial of anti-CD20 DNA vaccine in patients with relapsed or refractory lymphoma: “We have developed a clinical trial for patients with relapsed or refractory lymphoma, and we are in the final stages of attaining approval to begin the trial, which we anticipate will be in the early fall 2007, pending no request to changes to the protocol:The protocol was approved by the Department of Medicine Steering Committee, Research Council and passed initial IRB review at MSKCC (along with several other committees). The protocol was approved by the Recombinant DNA Advisory Committee of the NIH after public review and following minor modifications. A pre-IND teleconference with the FDA raised only minor concerns. Toxicity studies in rabbits are now completed and show no evidence of toxic effects.The CD20 vaccine to be used in the proposed study has been manufactured and vialed, and the GMP-manufactured product is being stored at MSKCC in the Pharmacy Department and ready for use following protocol approval by the FDA. An IND application was recently submitted to the FDA. The protocol is also simultaneously undergoing final reviews by the MSKCC Institutional Biosafety Committee and the Institutional Review Board. Bringing this vaccine to clinical trials has been challenging but we are delighted to report that the clinical trial should begin in the next few months.”

In December 2005 Dr. Houghton wrote: “A series of DNA vaccines against CD20 antigen expressed by lymphoma cells was tested in laboratory models.  The study showed that vaccination with a miniaturized CD20 gene from a different species could induce T cell responses, antibody responses, and result in long-term survival in a subset of immunized mice challenged with an aggressive lymphoma.  These results are the basis for studies that are moving forward with the New York Animal Medical Center to test this vaccine strategy in companion animals with lymphoma following cytotoxic therapy.  Most importantly, the Lymphoma Foundation has played a central role in our ability to move this strategy into the clinic.  A clinical trial has been written and submitted for review at MSKCC and development and manufacturing of a clinical grade CD20 DNA vaccine has begun.”

August 2002 : Dr. Houghton's commentary on the early work of his research team supported in part by Lymphoma Foundation grants: On August 20, 2002 Dr. Houghton wrote to the Lymphoma Foundation thanking the Lymphoma Foundation for its support of cancer vaccine research and he noted: “Given the recent success of monoclonal antibody therapy against CD20 on lymphomas,  Dr. Scheinberg and I, working in collaboration, have made much progress in the preclinical development of a DNA vaccine against the CD20 antigen on B-cell lymphomas. Members of the Scheinberg lab and Dr. Lia Palombo in our lab have established in principle that it is possible to induce active immunity against CD20, leading to tumor rejection in mouse models. Vaccination against self CD20 is very difficult, but we have recently found that we can trick the immune system into recognizing self CD20 by vaccinating with DNA encoding CD20 from a related species…” 

LYMPHOMA/STEM CELL TRANSPLANT SERVICE - Memorial Sloan Kettering Cancer Center

Lymphoma Foundation grants gave support to the following research data published by Dr. Craig Moskowitz and his colleagues:
Outcome of patients with primary refractory HD treated with high dose combined modality therapy and ASCT [Autologous Stem Cell Transplantation], C.H. Moskowitz, S.D. Nimer, T. Kewalramani, A.D. Zelenetz, J. Yahalom, British Journal of Haematology 2004, 124: 645-652

Rituximab Significantly Increases the complete Response Rate in Patients with Relapsed or Primary Refractory DLBCL Receiving ICE as Second-Line Therapy (SLT), T. Kewalramani, A.D. Zelenetz,  J. Bertino, G. Donnelly, E. Hedrick, A. Noy, O. O’Connor, C. Portlock, D. Straus, J. Yahalom, A. Gencarelli, D. Remy, J. Qin, S.D. Nimer, C.H. Moskowitz, Blood 2004 May 15; 103(10):3684-8

An update on the management of relapsed and refractory Hodgkin’s Lymphoma, C.H. Moskowitz, Seminars in Oncology 2004, 31: 54-59.

The age-adjusted international prognostic index predicts autologous stem cell transplant (ASCT) outcome for patients with relapsed or primary refractory diffuse large B-cell lymphoma -Paul A Hamlin, Andrew D Zelenetz, Tarun Kewalramani, Jing Qin, Jaya M Satagopan, David Verbel, Ariela Noy, Carol S Portlock, David J Straus, Joachim Yahalom, Stephen D Nimer, and Craig H Moskowitz*  BLOOD April 2003
They concluded: 'We evaluated the age-adjusted international prognostic index at the initiation of second-line therapy (sAAIPI) as a predictor of progression free survival (PFS) and overall survival (OS). The sAAIPI predicts outcome for patients with relapsed or primary refractory DLBCL in both intent-to-treat and chemosensitive populations. This powerful prognostic instrument should be used to evaluate new treatment approaches and to compare results of different regimens.'

RADIATION ONCOLOGY - Memorial Sloan Kettering Cancer Center
Joachim Yahalom, MD
Dr. Yahalom is an Attending Physician in the Radiation Oncology Department of the Memorial Sloan Kettering Cancer Center. The Lymphoma Foundation has supported many of his research projects and directs support to a post-doctoral Fellow working with Dr. Yahalom whose special interest is in the treatment of the lymphomas.
An important commentary concerning the continuing value of radiation therapy in the treatment of Hodgkin’s disease was published in February 2006 by Dr. Yahalom entitled: Don't Throw Out the Baby With the Bathwater: On Optimizing Cure and Reducing Toxicity in Hodgkin's Lymphoma Journal of Clinical Oncology, Vol 24, No 4 (February 1), 2006: pp. 544-548

Published research by Dr. Yahalom and his clinical research team supported in part by Lymphoma Foundation grants:: Intensity-Modulated Radiotherapy for Lymphoma Involving the Mediastinum, K.A. Goodman, S. Toner, M. Hunt, et al: Int J Radiat Oncol Biol Phys 62:198-206, 2005; Radiation Treatment Planning Techniques for Lymphoma of the Stomach,  C. Della Biancia, M. Hunt, E. Furhang, et al:  Int J Radiat Oncol Biol Phys 62:745-51, 2005; FDG-PET Scanning for Detection and Staging of Extranodal Marginal Zone Lymphomas of the MALT Type: A Report of 42 Cases, K.P. Beal, H.W. Yeung, J. Yahalom, Ann Oncol 16:473-80, 2005   Changing role and decreasing size: current trends in radiotherapy for Hodgkin's disease. Yahalom J. Curr Oncol Rep. 2002 Sep;4(5):415-23. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University,  New York, NY 10021  Rare variants of ATM and risk for Hodgkin's disease and radiation-associated breast cancers. Offit K, Gilad S, Paglin S, Kolachana P, Roisman LC, Nafa K, Yeugelewitz V, Gonzales M, Robson M, McDermott D, Pierce HH, Kauff ND, Einat P, Jhanwar S, Satagopan JM, Oddoux C, Ellis N, Skaliter R, Yahalom J. Clin Cancer Res. 2002 Dec;8(12):3813-9. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

ADDITIONAL LYMPHOMA FOUNDATION GRANTS TO THE MEMORIAL SLOAN KETTERING CANCER CENTER HAVE ALSO BEEN  DISTRIBUTED FOR RESEARCH BY THE FOLLOWING CLINICIAN/SCIENTISTS

UNIQUE AGENTS AND METHODS OF TREATING OVARIAN CANCER
Commentary by Paul Sabbatini, M.D. with regard to work in conjunction with Carol Aghajanian, M.D. and David Spriggs, M.D. -  Memorial-Sloan-Kettering-Cancer-Center

Mechanisms of and methods to overcome platinum resistance: The initial work supported [by the Lymphoma Foundation] in 2004-05 regarding the proteosome inhibitor borezomib is now summarized in "Clinical Update: Novel Targets in Gynecologic Malignancies" (C. Aghajanian: Semin Oncol 31 [suppl 16]: 22-26, 2004). To explore the hypothesis that inhibition of NF-K{3 with bortezomib renders ovarian cancer more sensitive to platinum agents, a phase I trial of bortezomib with carboplatin was completed and recently reported (C. Aghajanian, D Dizon, P Sabbatini, J Raizer, D Spriggs: J Clin OncoI23:5943-5949, 2005).

With regards to novel agents, we have just completed accrual of a trial of STI-571 (imatinib) for ovarian cancer patients in second or greater clinical remission (n = 35). Four patients remain on treatment and it is too soon for analysis. Based on the increasing interest in angiogenesis inhibitors in ovarian cancer treatment, we have IRB approval (and are awaiting IND application review) for a phase 1/11 trial of paclitaxel and carboplatin for patients with platinum sensitive recurrence in conjunction with increasing doses of PTK 787/ZK 222584. PTK (Novartis) is an oral selective inhibitor of the VEGF receptor tyrosine kinases VEGFR-1 and VEGFR-2.

The desire to investigate immune directed strategies directed towards CA-125 remains strong. We have now completed an open label, phase I study evaluating two doses and routes of the anti-idiotypic monoclonal antibody ACA-125 (anti-id mAb ACA125). We currently are participating in the organization of an international randomized study of the anti-id mAb ACA125 for patients in first clinical remission.

Finally, we have now accumulated sufficient numbers of patients on multiple phase I trials of monovalent vaccines in remission patients to begin to evaluate the characteristics of the population, and to compare the clinical characteristics of the combined vaccine population to historical populations of patients not receiving vaccine therapy. The endpoints of these studies have been safety and immunogenicity.

LYMPHOMA FOUNDATION GRANTS HAVE ALSO BEEN RECEIVED BY OTHER MAJOR CANCER CENTER CLINICIAN/SCIENTISTS
 

Christopher M. Counter, Ph.D.

The following is Dr. Christopher Counter’s ‘Introduction’ to his research proposal to the Lymphoma Foundation concerning the role of the TELOMERE in aging and cancer formation.

“Telomere shortening and aging. Human ageing is a complex process, of which one component may be a decline in the proliferative potential of cells. Specifically, human cells isolated from older donors divide for a shorter period of time in culture than those from younger individuals. A critical mechanism governing the lifespan of cells in culture (in vitro), and likely also in the body (in vivo), is telomere length. Telomeres are DNA/protein complexes that cap and protect the ends of eukaryotic chromosomes from illegitimate recombination and degradation. As normal human somatic cells divide in vitro, their telomeres shorten until a critical length is reach that signals a growth arrest termed senescence. Similarly, as humans age there is a decrease in telomere length in the somatic tissues. This telomere shortening may limit the ability of human cells to regenerate tissues after years of use. Indeed, excessive telomere shortening in mice causes some aging phenotypes and in humans is thought to play a role in the disease dyskeratosis congenital, which is characterized by a decrease in the proliferative potential of certain tissues. Moreover, cells from patients with premature aging syndromes like Hutchinson-Gilford Progeria and Werner’s Syndrome have shorter or abnormal telomeres compared to age-matched controls. Telomere shortening in vascular cells has also been implicated in atherosclerosis, a disease associated with aging.  Understanding how telomeres length is controlled should provide important  insight into the molecular clock that governs the replicative potential of cells, and ultimately the process of ageing itself.”

OTHER RECIPIENTS OF SUPPORT FROM LYMPHOMA FOUNDATION GRANTS

ADDITIONAL GRANTS 
Beginning in 1990 an annual Lymphoma Foundation grant has been distributed to
 
The National Library of Medicine

This annual grant by the Lymphoma Foundation in conjunction with many other unique donors formed a major contribution to the initial development of 'Grateful Med' the National Library's initial fee for service internet database that evolved into Medline.  Now the use of this dramatically expanded database is available as a free internet service (also known as Pub Med and Gateway) that allows all persons to easily access hundreds of thousands of abstracts of medical literature.

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