SUMMARY REPORTS OF EXCHANGE SCIENTISTS

(1) Kazuo Tamura
Department of Internal Medicine
Miyazaki Prefectural Hospital

Sponsor and Host Institution:
Dr. T. Ohnuma, Department of Neoplastic Disease Mount Sinai School of Medicine, New York
Dr. E. Henderson, Department of Medical Oncology Roswell Park Memorial Institute, Buffalo
Dr. R. Storb, Fred Hutchinson Cancer Research Center, Seattle
Dates of Visit:
8/20-8/30/88: Mount Sinai Medical Center, City Hospital Center at Elmhurst Memorial Sloan-Kettering Cancer Center
8/31-9/4/88: Roswell Park Memorial Institute
9/5-9/9-88: Fred Hutchinson Cancer Research Center

Summary of Activities
I visited three major cancer centers in the United States to see recent advances in cancer chemotherapy and bone marrow transplantation.
At Mt. Sinai Medical Center, they have made multicellular tumor spheroids (PC10, a cell line of squamous cell carcinoma of the lung and HEp2, a cell line of squamous cell carcinoma of the larynx) to determine the degree of the drug penetration into these spheroids by autoradiography. The reason why they use spheroids instead of using single cell suspensions is that spheroids have certain characteristics similar to solid tumors which are more commonly encountered in clinical practice. Previously they screened various agents for cell lethality by using these spheroids and clonogenic assay showing that a combination of cisplatin and cytarabine was synergistically effective against the tumor cells. Now, nude mice have been treated with this combination following innoculation of the above tumor cells to see whether it really works.
For drug resistance, protein kinase C, which has an important role on regulating p-glycoprotein, has been analyzed by a protein-dye binding method in a resistant breast carcinoma cell line. They have also tried to extract multi-drug resistance gene from MOLT-3/TMQ800 and MOLT-3/TMQ2500.
Dr. Rustum's group at Roswell Park Memorial Institute have found that when 5FU is administered after priming with leucovorin, they strongly inhibit thymidylate synthase. Leucovorin 25-500mg/m² has been given followed by 350-600mg/m² to the patients with advanced carcinoma, especially colon cancer. The overall response rate has been around 50 percent with response duration of 12-15 months for partial responders and 20+ months for complete responders. There has also been some responses in patients who had already acquired resistance to 5FU.
I am somewhat disappointed that major cancer centers have not heavily become involved in developing new antineoplastic agents or new modalities of treatment to overcome the drug resistance and break through the stagnation of progress in clinical oncology. I was rather impressed by Prof. G. Mathe from France who visited Mt. Sinai on 8/26/88 and gave us a talk entitled "Cancer Therapy Outlook for the Next Decade." He presented information on new drugs and modalities of treatment, i.e. oxoferin, D-Trp6 (LH-RH analogue), 1-OHP (Platinum derivative), poly A,U, zinc gluconate, bestatin, neo-adjuvant therapy, and autologous bone marrow transplantation.
Acquired immune deficiency syndrome (AIDS) is one of the most serious problems in public health in the United States. Especially New York City, which has the largest number of AIDS patients who have disrupted the health care system with financial overload.
The Interagency Task Force on AIDS of the City of New York has published a large book of strategic plans for AIDS. Eight to nine large institutes in New York City are participating in NIH-sponsored AIDS program. I had a chance to visit an AIDS unit and AIDS clinic at Mt. Sinai Medical Center and Elmhurst General Hospital. According to ATEU protocol, zidovudine (AZT), foscarnet, and AL721 have been used for HIV infected individuals, AIDS related complex, or other AIDS related conditions, and fluconazole is being compared with amphotericin B for cryptococcal menningitis.
Bone marrow transplantation (BMT) has acquired an important position in treating hematological malignancies, some solid tumors, and aplastic anemia. In most of the centers, including Fred Hutchinson Cancer Research Center in the United States, regular rooms are used for HLA-identical BMT in patients with malignant diseases and laminar air flow rooms with sterile techniques are used for HLA-mismatched BMT and aplastic anemia. When the patients are admitted to the BMT units, the Hickman catheter is inserted into the subclavian vein for administering intravenous fluids, antibiotics and blood products, and drawing blood. For pre-BMT conditioning, hyperfractionated TBI (120x12 rad), 200/dayx6 rad, and 225/dayx7 rad TBI have been studied in conjunction with administration of high-dose cyclophosphamide. After BMT, the patients are given cyclosporine A and methotrexate for graft versus host disease (GVHD) which appears to be better controlled than before. Elimination of T cells from the donor's bone marrow to reduce the incidence of GVHD has been discouraged because of increased rejection and leukemia relapse. It seems that T-cell purging loses graft versus tumor (leukemia) effect resulting in increased leukemia relapse. Veno-occlusive disease (VOD) is one of the severe complications, and there have been no good treatment for VOD except for supportive care including maintaining the hematocrit level to around 40 percent, albumin, diuretics, and a low dose of dopamine. Nosocomial infection, especially fungal and viral infection, and interstitial pneumonitis are still a challenging problem. Antifungal agents, mainly amphotericin B and antiviral agents, acyclovir, have been commonly used. A randomized trial with a high dose of gammaglobulin as a prophylactic agent has just finished. It showed that the first local infection, first sepsis, and GVHD seem to be decreased in frequency with a treated group, but overall survival was same in both groups. Gammaglobulin is a very expensive drug and its cost must be considered over its marginal effect. It is of interest that bone marrow has been treated with 12.8 antibody to pick up stem cells or with antitumor antibody to pick up stem cells or with antitumor antibodies such as CALLA to eliminate the abnormal cells before autologous bone marrow is infused to the recipient. This carries an unexpected delayed bone marrow recovery, the cause of which remains to be studied. Nevertheless, Iong-term survival of around 50 percent has been reported in allogeneic BMT for severe aplastic anemia, thalassemia, Fanconi's anemia, myelogysplastic syndrome, chronic myelogenous leukemia in chronic phase, and acute leukemia in first remission. Autologous BMT and HLA-mismatched allogeneic BMT are still experimental in most of the BMT centers.
I gave a lecture regarding HTLV-1 related diseases in three institutes. They were interested in my talks, especially in MSMC and Elmhurst General Hospital where they have a lot of AIDS patients.
In the field of chemotherapy, new antineoplastic agents seem to be investigated to a limited extent in centers which I visited. During resistance studies have moved towards p-glycoprotein and multi-drug resistance gene, but it will take a while to introduce these studies to the clinical practice. Drug modulation with 5FU and leucovorin is one of the interesting approaches to increase the response rate with a prolonged duration of response. It may be worthwhile to study this combination consisting of oral 5FU derivatives and oral leucovorin in Japan since oral 5FU derivatives are being commonly used in Japan.
Since there are no hospitals in the southern part of Kyushu which are actively doing bone marrow transplantation, we would like to start it in our hospital as soon as possible. Before we start it, it was very lucky that I was able to learn recent advances in bone marrow transplantation which really helps me to open up a new bone marrow transplant unit in our hospital. We should be able to do the first transplant at the end of this year.
It was my great pleasure that I was able to meet and know many distinguished researchers and clinicians through this program, and it is possible to do cooperative studies such as oral 5FU-Ieucovorin combination therapy. I should also be able to call them when I really have difficult problems for our patients which might be solved by them.



(2) Shigetaka Asano
Department of Hematology-Oncology
Department of Pathological Pharmacology
Institute of Medical Science
University of Tokyo
6-1, 4 Shirokanedai Minatoku
Tokyo 108

Sponsor and Host Institution:
Dr. Gary Spitzer, M.D. Anderson Hospital and Tumor Institute University of Texas, Houston
Dr. James N. Ihle, St. Jude Children's Hospital, Memphis
Dr. Karen H. Antman Dana-Farber Cancer Institute, Boston
Dr. Malcolm Moore, Memorial Sloan-Kettering Cancer Center, New York
Dr. Karl G. Blume, Stanford University Hospital, Stanford
Dates of Visit: December 2, 1988 - December 21, 1988

Summary of Activities:
The objective was to get detailed information on recent advances of autologous bone marrow transplantation for cancer treatment. After attending THE AMERICAN SOCIETY OF HEMATOLOGY ANNUAL MEETING at San Antonio, I visited 8 hospitals and institutes. In each place I could discuss mutually interesting subjects with many active medical doctors and researchers. The main subjects were (1) ex vivo manipulation of malignant cells in autografts with monoclonal antibodies and chemotherapeutic agents, (2) in vitro expansion of pluripotent stem cell population using various hemopoietic factors, (3) new preparative regimens with less non-hematopoietic tissue toxicity, and (4) clinical application of various recombinant hemopoietic factors including G-CSF, GM-CSF, II-1, IL-3, and IL-6 alone in combination. Through the discussions, I got many useful suggestions for future directions of our own research concerning autologous bone marrow transplantation. In addition, I had two opportunities to give a lecture on G-CSF.
Additional Comments:
1. Their experience in the clinicai use of GM-CSF for autologous bone marrow transplantation for breast cancer has been helpful for making out new protocols using our G-CSF.
2. The purification technique of hemopoietic stem cells purification and SCID mice will be ready to use in our own research projects.
3. I feel that my efforts have contributed to the progress of the NCI-JSPS Cancer Program by better understanding the advances which have recently been achieved in the U.S.A.



(3) Kohji Ezaki
Fujita-Gakuen Health University School of Medicine

Sponsor and Host Institution:
Dr. Jordan U. Gutterman, Department of Clinical Immunology and Biological Therapy, University of Texas, M.D. Anderson Cancer Center
Dates of Visit: March 12, 1989 to April 1, 1989

Summary of Activities:
Biological response modifiers (BRMS) such as IFN, IL-2 and TNF, have been introduced in the treatment of malignant disease. Although some of these BRMs shows the significant antitumor activity, the target tumors are generally limited. To establish more effective ways of using BRMs, we have to know the mechanism of antitumor activity of these agents and also the optimal dose schedule for clinical use (including combination treatment). With this scientist exchange program, I had the opportunity to visit 3 institutions: M.D. Anderson Cancer Center, Arizona Cancer Center, and NCI, Frederick, all of which have BRM research and clinical activities, and to discuss the possible future for BRMs in cancer treatment.
Dr. Gutterman and his group in M.D. Anderson Cancer Center have a profound experience with IFNs and other BRMs. They treated hairy cell leukemia (HCL) with IFN- for the first time, which is now known to be the most effective agent for HCL. Lately they reported another disease, chronic myelogenous leukemia (CML), in which IFN has clinical efficacy. Their current results with IFN-²A for 45 CML patients shows that hematological CR was obtained in 33 patients (73%) and cytogenetical response in 22 patients (49%). The complete disappearance of Ph¹ chromosome was seen in 8 patients, in whom bcr/abl rearrangement was not detected by western blotting. Even with most intensive chemotherapy, Ph¹ chromosome is rarely abrogated and CML was known to have poor prognosis with median survival of 3-4 years. The fact that IFN can induce the disappearance of PH¹ chromosome is, therefore, noteworthy and IFN may play a major role in the treatment of CML.
Because the single agent efficacy of IFN and other BRMs is limited, investigators are trying to establish the effective combination treatment using BRM and anticancer agents. They applied multiple combination regimens, but the clinical efficacy has not generally been striking. Among them the combination of IFN- and 5FU is interesting. This combination treatment was initiated in Albert Einstein Cancer Institute, after observing the synergistic effect in human colon cancer cell line and a significant clinical efficacy was reported against various adenocarcinomas. In M.D. Anderson Cancer Center, they used same combination schedule, and obtained 1 CR and 13 PR among 18 previously non-treated colon cancer patients. The synergistic effect of IFN- and 5FU seems to be confirmed and the mechanism of this effect need to be clarified.
Combination treatment among BRMs such as IFN- + IL-2, IFN-r + TNF, IFN-r + CSF, and so on are also progressing clinically for various types of malignancies. Most of these trials are too immature to determine efficacy.
GM-CSF is known to increase the number of granulocytes and is used extensively in various types of malignancies to see if it is possible to increase the dose of anticancer agents and to enhance the antitumor activity. In in vitro studies, the growth of leukemic cells was stimulated with the addition of GM-CSF and there are some fears that GM-CSF may aggravate the leukemic process. In fact, some AML patients have an increment of leukemic cells with the administration of GMCSF, but this is usually temporal phenomenon. If many leukemic cells are provoked into growth fraction by GM-CSF, antitumor effect could be augmented. This might be an interesting treatment approach to some types of leukemia. There are some difficulties in pursuing the clinical trials of combination treatment. First, some BRMs Such as IFN- and TNF are very active in animal tumor models but these agents have little efficacy in human tumors. Thus, the clinical effects do not reflect the results observed in vitro study or animal experiment. Second, the administration of a BRM may unpredictably influence the activation or suppression of another BRM, which makes the evaluation of any single BRM difficult. Even with these problems, it is important to get the basis for clinical combination treatment from the animal experiments. Another approach will be to try various combination schedules which seem to be effective and to characterize the mechanism of action through the evaluation of effective cases.
Biological therapy will play a much more important role in cancer treatment. From the careful preclinical studies and well-organized clinical trials, we will be able to find the way to control cancer by BRMs.