STATEMENTS FROM CLINICIAN SCIENTISTS
“IN THEIR OWN WORDS”

INTRODUCTION TO CLINICIAN SCIENTISTS SUPPORTED WITH LYMPHOMA FOUNDATION GRANTS

M. LIA PALOMBA, MD
GARY K. SCHWARTZ, MD
STEPHEN NIMER, MD
RAYMOND COMENZO, MD
MORTIMER J. LACHER, MD

M. LIA PALOMBA, MD

“For the past 8 years, I have worked on developing novel immune therapies for lymphoma. I have been particularly interested in developing active immunization through tumor vaccination. The goal is to render the patients harboring lymphoma (or at high risk for recurrence) to be able to mount a response to any residual or re-emergent lymphoma cells. To do that, we selected a lymphoma protein named CD20 that is the target of a commonly used monoclonal antibody, Rituximab. From the Rituximab experience, we know that CD20 is a good target, but since CD20 is a normal component of some cells of the immune system, it would normally not be recognized as foreign by the immune system. We used various techniques to be able to trick the immune system and make it able to recognize CD20 and kill lymphoma cells, through the generation of a special type of immune cells with killing activity. While we are working on constructing a second generation CD20 vaccine with higher potency, we have opened a clinical trial to test the activity of the current vaccine in patients with residual, recurrent or refractory lymphoma who have received at least one line of conventional treatment. The trial is currently accruing at MSKCC.  More recently, my interest has expanded to include the study of the molecular mechanisms involved in the development of chronic lymphocytic leukemia, which can be regarded as a subtype of indolent lymphoma.”  August 2009

GARY K. SCHWARTZ, MD

As a physician/scientist at Memorial Sloan-Kettering Cancer Center, I have spent my career directing phase I clinical trials based on preclinical discoveries made in my laboratory.   The laboratory has focused on the identification of small molecules that block specific signaling pathways in tumor cell so as to enhance the effects of chemotherapy.   We were the first to report that inhibitors of the protein kinase C pathway (safingol and bryostatin-1) enhanced chemotherapy induced apoptosis.   We later determined that the cell cycle inhibitor flavopiridol enhanced chemotherapy- and radiotherapy-induced apoptosis in a sequence specific manner.    For example, when flavopiridol was administered before paclitaxel, it induced a G1 and G2 cell cycle arrest, such that cells were unable to advance to mitosis and undergo the mitotic exit required for apoptosis.  This process, which we termed “cell cycle resistance”, has had a significant impact on the design of clinical trials evaluating cell inhibitors with chemotherapy today.  We were the first to report that inhibitors of the Chk1 pathway enhance the effects of topoisomerase I inhibitors in both a p53 and a sequence dependent manner.  We were the first to show that the MDM2 inhibitor Nutlin-3a enhanced the activity of several chemotherapeutic agents in cells with mutant p53.  More recently we have reported that inhibitors of gamma secretase promote chemotherapy induced apoptosis.   Each of these laboratory studies has been translated from the benchtop to the bedside and I direct a phase I program that provides new approaches and hope for my patients with advanced cancers.  August 2009

STEPHEN NIMER, MD

I have worked as a hematologist/oncologist for the last 25 years, focusing on the care of patients with hematologic cancers and with bone marrow that does not function normally such as patients with aplastic anemia and myelodysplastic syndromes. I have led clinical investigations of hematopoietic growth factors and immunosuppressive therapies to try to stimulate the bone marrow of patients with these diseases, and of bone marrow or stem cell transplants (autologous and allogeneic) to eradicate hematologic malignancies or cure bone marrow diseases. More recently, we have used transcriptional modifying therapies like histone deacetylase inhibitors and hypomethylating agents to treat these diseases, and this area of research remains a critical focus of our efforts. Over the past 17 years while at Memorial Sloan-Kettering, I established the autologous stem cell transplant program for hematologic malignancies. This program has focused primarily on treating patients with lymphoma (both non-Hodgkin and Hodgkin lymphoma) and patients with multiple myeloma. In addition to evaluating novel high-dose therapies for these diseases, we have established several research programs using investigational agents to target the molecular abnormalities found in myeloid malignancies like acute myelogenous leukemia (AML).
My research interests coincide with my clinical interests. My laboratory is investigating the molecular defects that underlie the myeloid malignancies such as AML, myelodysplastic syndromes, or myeloproliferative diseases, including chronic myelogenous leukemia. My laboratory has cloned several genes involved in blood formation and has extensively characterized the most common translocation (exchange of chromosomes) found in acute leukemia, the t(8;21). More recently we have broadened our focus to understand how cancer cells resist chemotherapy or radiation therapy. As part of this effort, we have become a member of the Brain Tumor Center in order to study aspects of glioblastoma multiforme biology. In 2001 we received one of two awards given to U.S. investigators by The Leukemia & Lymphoma Society as a Specialized Center of Research in myeloid malignancies. This award was renewed in 2006 for another five years. I have been active in national hematologic organizations and currently serve on the Board of the Bone Marrow Foundation; the Aplastic Anemia and MDS International Foundation, Inc.; the Myelodysplastic Syndrome Foundation; and I am Chairman of the Medical Advisory Board of the Gabrielle's Angel Foundation for Cancer Research. I have been a member of the American Society of Clinical Investigation since 1997. August 2009

RAYMOND COMENZO, MD

My career has been focused on advancing the knowledge and treatment of plasma cell diseases such as light-chain (AL) amyloidosis and multiple myeloma. In my laboratory we discovered the links between the tropism of AL organ disease and immunoglobulin light-chain germline donors in the clonal plasma cells. This was an important discovery because it provided researchers with the basis for developing animal models of AL, an enterprise that continues in numerous laboratories around the world. In my laboratory, we also discovered that the clonal plasma cells in AL express the B-cell antigen CD32B, a potential target for immunotherapy. We also discovered that patients with amyloid could have 2 potential sources of amyloid-forming proteins creating a risk of misdiagnosis of AL, and that lymphomas cause AL by secreting free immunoglobulin light chains. In my clinical research, we established that autologous stem cell transplant is feasible and effective in AL and monoclonal light chain deposition disease; that novel agents used after stem cell transplant for AL improve responses; and that single-agent bortezomib is particularly effective in relapsed AL. These findings were all based on the results of prospective clinical trials. Most recently, in my laboratory, we have discovered that the clonal plasma cells of patients with AL segregate into two groups based on expression levels of cyclin D1 (CCND1). Those with high expression of CCND1 have poorer survival than those with low expression, due to early onset of cardiac amyloid likely the result of higher free light chain levels (ASH 2009). This observation is being further examined in the context of 2 phase III trials, one in the USA (ECOG 4A08) and the other in the EU, both of which compare standard therapy with oral melphalan and dexamethasone (MD) to MD plus bortezomib for newly diagnosed patients with AL. September 2009

MORTIMER J. LACHER, MD

At the Lymphoma/ Myeloma Meeting in New York City at the Grand Hyatt Hotel on October 16, 2004 there was a  Special Award Ceremony

The John Ultmann Award for Outstanding Contributions to
Patient Care, Research and Education
 in the Lymphomas

Recipient: Mortimer J. Lacher, MD, The Lymphoma Foundation

Presenters: Morton Coleman, MD, Ruth Ultmann

The following are the remarks made by Dr. Lacher on receiving the John Ultmann award:
 

Mrs. Ruth Ultmann, Dr. Morton Coleman and colleagues, I am deeply honored to receive the John Ultmann award and I would like to thank you for the privilege of equating my career in lymphoma/hematology with that of the late Dr. John Ultmann who dedicated a large part of his life caring for patients with lymphoma and doing the research that contributed to better treatments for patients with lymphoma and leukemia… until he, himself, succumbed to lymphoma.

I inter-acted directly with Dr. Ultmann when we co-authored an American Cancer Society monograph on Hodgkin’s and non-Hodgkin’s Lymphoma.  But for the better part of our lives I knew John… only at a distance… meeting him vicariously from time to time in the many papers he co-authored with his clinical research team at the University of Chicago. We shared a mutual colleague, however, Dr. Sam Hellman, who came from Boston to be part of the Memorial Sloan Kettering Cancer Center (MSKCC) bringing with him the concept of lumpectomy to treat breast cancer that replaced the many years of radical and super-radical mastectomy promoted by the grand master surgeons at MSKCC. Dr. Hellman then moved on to the University of Chicago where Dr. Ultmann had already distinguished himself as Professor in the Department of Medicine and Director of their Cancer Research Center.

I had a special place in my academic heart for John Ultmann as I fought to maintain my role as patient advocate to treat lymphoma patients and especially Hodgkin’s patients with a new approach to chemotherapy… because John Ultmann was one of my astute colleagues who recognized the extraordinary position that Dr. Durant and I occupied in 1965, as the first to publish the value of using multiple drugs simultaneously, rather than just a single drug to treat Hodgkin’s disease. 

It may seem strange to this audience of young oncologists that the concept of multi-drug chemotherapy had to be invented and that the method, multi-drug therapy, was not always ‘routine’ as it is today.

What is even more extraordinary is the fact that the days of multi-drug chemotherapy as we know it today are numbered and I may actually live long enough to see the full blooming of the new wave of targeted biological therapy become the only way to treat all  lymphomas and for cancer in general. The monoclonal antibody, rituximab led the way in achieving greater treatment success for patients with non-Hodgkin’s lymphomas… even if it did take a half century of development to go from an extraordinary laboratory observation to a practical clinical application… and now there are many other monoclonal antibodies being used and many more in the research pipeline.

Radical surgery for breast cancer is now mocked by young generations of oncologists. Chemotherapy, multi-drug chemotherapy, will eventually give way to more specific “targeted” biological treatments and soon, yes, soon… my radiation therapy advocates, you, too, will be put out to pasture converting… to another…  yet to be invented…  unique specialty… as your giant x-ray machines are relegated to the back rooms of the Smithsonian Museum. One of the first Betatron machines from Memorial Sloan Kettering is already there… and I…  as a compassionate radical … continue to strongly advocate the need to find better ways to treat all patients with therapies that will not lead to their early death from complications induced by our treatment.

Once again, we are at an important set of crossroads in human history.

In the case of medical history each crossroad usually means a step forward in understanding and an improvement in the way humans survive.

In medical history, in the treatment of the lymphomas and cancer in general… we stand at the threshold of a great and wonderful leap forward.

Thank you again for this honor in receiving the John Ultmann award.

SEE: SCIENTISTS PAGE and  then read the following about the further development of multi-drug chemotherapy for Hodgkin's disease... from Velban Chlorambucil to MOPP - [Nitrogen] Mustard, Oncovin, Procarbazine, Prednisone

A follow-up regarding the development and application of multi-drug chemotherapy with special credit to the National Cancer Institute and DeVita, et al..as stated in the First and Second Editions of CHEMOTHERAPY OF CANCER by S.K.Carter, M. T. Bakowski and K. Hellman - John Wiley & Sons Publishers

“At about the same time, pioneering work on combination chemo­therapy for hematologic malignancies, including lymphoma, was underway at the National Cancer Institute ( NCI) under the leader­ship of Zubrod, Frei and Freireich.  The first NCI combination for Hodgkin's disease included cyclophosphamide, vincristine, metho­trexate, and prednisone given in three 2-week courses and combined with radiotherapy between the first and second course in patients with stage I to IIIA disease. Patients with stage IIIB, and some with IIIA, were treated by chemotherapy alone.  All the patients (9/9) who received chemotherapy plus radiotherapy achieved complete remission, while there were three complete and two partial remissions in five patients treated by chemotherapy alone.  The overall response rate of 100% in this pilot study demonstrated for the first time the feasibility of an aggressive combined modality approach to therapy.  Based on this experience further approaches were made to devise an optimum combination of active agents without overlapping or undue toxicity. The culmination of these efforts was the "MOPP"protocol devised by DeVita et al. at the NCI.”

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