SUMMARY REPORTS OF EXCHANGE SCIENTISTS

(1) Takeshi Ogura
The University of Tokushima School of Medicine, Tokushima 770, Japan

Sponsor and Host Institution:
Dr. Isaiah J. Fidler
University of Texas System Cancer Center M.D. Anderson Hospital & Tumor Institute Houston, Texas
Dates of Visit:
October 4-18, 1988

Summary of Activities:
Objectives of Visit: Discussion of the present status and future prospect of immunotherapy with cytokines and related BRM in lung cancers.
I. Harvard Medical School and Massachusetts General Hospital
A Discussions on problems in adoptive immunotherapy with IL-2-activated cytotoxic lymphocytes.
1. Induction of CTL from TIL of lung cancer tissue, with Dr. J. T. Kurnick.
2. Clinical effect of adoptive immunotherapy with IL-2-activated TIL and IL-2, with Dr. R. L. Kradin.
B. Seminar lecture: Interleukin 2-activated lymphocytes in the immunotherapy of lung cancer.
C. Review of clinical response of lung cancer on chest x-gram to TIL-LAK therapy in MGH, with Dr. R. L. Kradin.
II. University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute
A. Discussions on Cancer Immunotherapy
1. Clinical effect of immunotherapy with TIL-LAK and cytokine (IL-2, TNF, IFN), with Dr. D. Parkinson
2. Induction of cytotoxic lymphocytes from TIL, with Dr. K. Itoh.
3. Phase I trial of liposome-MTP, with Dr. J. L. Marray.
4. Experimental and clinical effect of combined use of IL-2 and TNF, with Dr. E. A Grimm
5. Pilot Study of intrapleural interleukin-2 in patients with malignant pleural effusion, with Dr. P. Y. Holoya
6. Cytological and molecular change in macrophages activated with liposome-MTP, with Dr. E. Kleinerman.
7. Future trends of clinical immunotherapy, with Dr. I. J. Fidler.
B. Seminar: Immunomodulating effects of monocytes-macrophages on IL-2-activated lymphocytes: Potential therapy of patients with lung cancer.
III. NCI Frederick Cancer Research Facility
A. Observation of RFLP study on tumor suppression gene in small cell lung cancer and renal cancer.
B. Discussion of future trend in cancer prediction, with Dr. B. Zbar.
C. Discussion of problem of LAK therapy, with Dr. J. H. Ortaldo.
In order to help us improve the program, please answer the following questions:
1. Has the program assisted you in achieving your research objectives?
I am pleased to know the details of recent progress of cancer immunotherapy in the U.S.A and the future trend in cancer immunology.
2. How could progress in your research effort be enhanced through this program?
I would like to keep the communications with the doctors who have been kind to discuss and inform in earnest.
3. How do you feel your efforts have contributed to the progress of the NCI-JSPS Cancer Program?
I think my visit was a part in introducing the present status and our general concept of cancer immunotherapy in Japan. Personally, I appreciate having instructive discussions in seminars on our recent data on the role of monocytes-macrophage in control of the induction of tumorcidal lymphocytes by IL-2. The data have been published in some international journals.



(2) Toshimitsu Uede
Department of Pathology, Sapporo Medical College, Sapporo, Japan

Sponsor and Host Institution:
Dr. Steven J. Burakoff
Professor of Pediatrics
Harvard Medical School
Dana-Farber Cancer Institute
Dr. Alan N. Houghton
Head, Laboratory of Solid Tumor,
Melanoma-Sarcoma Section
Division of Medical Oncology
Sloan-Kettering Cancer Center
Dates of Visit: February 2, 1989 to February 19, 1989

Summary of Activities:
1. To facilitate the characterization of a unique T cell antigen (8H3) defined by our monoclonal antibody; especially to clarify the relationship of 8H3 antigen with other integrin family molecules.
2. To clarify the role of integrin molecules in T cell activation. It seems that 8H3 antigen may represent a new member of integrin molecules. To prove this point, Dr. Hemler and I exchanged the reagents. Concerning the functional role of integrin molecules, the role of integrin for T cell activation has been overlooked or underestimated. However, binding of thymocytes to a synthetic peptide which contains RGD sequence was specifically inhibited by 8H3 antibody and the crosslinking of 8H3 antigen initiated Ca²⁺ influx, phosphorylation of 8H3 antigen, and induced T cell proliferation. Dr. Chikao Morimoto at Dana-Farber also presented the evidence that T cell proliferation induced by anti-T3 antibody requires the presence of extracellular matrix. These data collectively shed the new light on the functional importance of integrin molecules. In addition, Dr. Tony Albino, Sloan-Kettering Cancer Center, and I agreed that the expression of alpha chain of VLA is different between original tumor tissues and metastatic tumor tissues. It will be interesting to investigate if there is any correlation between the pattern of alpha chain expression and metastatic sites.
1. Has the program assisted you in achieving your research objectives?
It was critical to compare the real results and make a face-to-face discussion to clarify the nature of 8H3 antigen. Furthermore, unpublished results became available only after serious discussion.
2. Do you plan to continue your collaboration?
Certainly I would like to continue with Dr. Morimoto and Dr. Hemler. At the same time, it would be very nice if the extension of stay in host's laboratory becomes possible in the case that collaborative study is really required after short stay



(3) Yujiro Higashi
Cancer Institute, Japanese Foundation for Cancer Research

Sponsor and Host Institution: Dr. Harry V. Gelboin
National Cancer Institute
National Institutes of Health
Dates of Visit: September 26, 1989 to October 1, 1989

Summary of Activities:
In the laboratory of Dr. Harry V. Gelboin at NCI, I could discuss the ongoing studies on various cytochrome P-450s, such as debrisoquin-metabolizing P-450 (P450db1), Ethanol-inducible P-450 and brain-specific P-450. They are analyzing the structures of those cytochrome P-450s by cloning of their cDNAS and genes. I intensively discussed the results of studies on the genetic difference in P-450db1 activity among human population (there are low- and high-metabolizer of debrisoquin in man), because the genetic situation (gene organization, or frequency of defective phenotype in man) is very similar to the case of my study on cytochrome P-450(c21) (sterioid-21-hydroxylase) deficiency, one of the most common inborn errors of metabolism. I gave a seminar of the molecular genetic analysis on P450(C21) deficiency, and we had the fruitful discussion on the results of their expression systems for the cDNAs using vaccinia virus vector, and they provided me the protocol and materials for my future experiments.
1. Has the program assisted you in achieving your research objectives?
Yes, as I mentioned above, I found their expression system are very effective, and they provided me with the systems, which will certainly assist my future experiments.
2. How could progress in your research effort be enhanced through this program? Do you plan to continue your collaboration?
Yes, I could know the similar results on the P-450db1 to my study on the P450(C21) deficiency. I think the two cases are very important findings in human genetics.
3. How do you feel your efforts have contributed to the progress of the NCI-JSPS Cancer Program?
My present study does not have direct contribution to cancer research, but I think its genetic aspect has very important results in considering the role of mutation in tumorigenesis. This time, I could visit Dr. Gelboin's lab by this program and found it very meaningful for each other to have a talk about our recent progress.