REPORTS ON SEMINARS
(1) Seminar on “Immunobiological Approaches to the Treatment of Cancer”
The focus of the Nagoya seminar March 28-29. 1996, was the use of emerging immunobiological information and advances in biotechnology in innovative approaches to cancer therapy. Following introductory remarks from Dr. Makoto Ogawa, Acting President of Aichi Cancer Center, Nagoya, and Dr. David R. Parkinson, Acting Associate Director of the Cancer Therapy Evaluation Program, National Cancer Institute, the initial presentations in the first two sessions concerned newly-identified tumor-associated antigens and their use in formulating new immunization strategies in patients with cancer.
Dr. Kyogo Itoh presented his work concerning the identification of tumor-rejection antigens associated with human squamous cell carcinoma. He initially presented a summary of the many advances in identification of human melanomas, and then proceeded to show that the same strategies had been used successfully by his research group to isolate similar antigens from squamous cell carcinoma cell lines, These antigens have served as the targets for cloned tumorspecific HLA Class I-restricted cytotoxic T lymphocytes; the genes for several of these antigens have been cloned. Similar approaches appear to be successful with respect to isolation of antigens from gastric, lung, and colon adenocarcinomas.
Dr. Martin Sanda then discussed prostate carcinoma as a target for immunobiological-based treatment strategies. He showed data relevant to the nature of major histocompatibility antigen Class I processing in prostate cancer cells, and the effects on immunogenicity of these cells with transfection by GM-CSF. He described a recently activated Phase I clinical trial at the University of Michigan involving autologous cells isolated at prostatectomy and subsequently transfected with GM-CSF as a basis for immunization. He then also discussed the evidence for bcl-2 overexpression in prostate cancer, and potential strategies for inducing apoptosis selectively in prostate cancer cells which are being explored preclinically.
Dr. Yasafumi Kaneda discussed the use of cationic liposomes to increase the efficiency of transfection of viral vectors in gene therapy, or of anti-sense oligonucleotides as therapeutic anticancer agents. In particular, a liposome incorporating inactivated Sendai virus (HVJ, hemagglutinating virus of Japan) was shown preclinic211ly to have 21 number of advantages therapeutically.
Dr. Pat Geraghty discussed the use of dendritic cells pulsed with intact tumor cells, tumor lysates, or acid-stripped tumor antigens in novel cancer immunization treatment strategies. Dendritic cells represent the most efficient antigen-presenting cells, and such strategies may potentially augment a stronger and broader T-cell response than some of the other immunization approaches being examined. Clinical trials using this methodology are currently under development at the University of Michigan.
Dr. David Parkinson then described the NCI clinical developmental program for cancer vaccines. He presented the reasons for the current strong interest in this area, referring back to some of the immunobiological principles described by Dr. Itoh. He described the range of antigens being used as bases for vaccine development, and the varied nature of the manners in which the antigens are being present, including either as whole proteins, or in oligopeptide epitopes, as genes integrated into vaccinia, fowlpox, or baculovirus vectors. The complexities of formal clinical development in the setting of many antigens, many more epitopes within these antigens genetic restriction of immune responsiveness to the antigens, many potential immunization strategies, alternative possibilities for vaccines adjuvants and the use of adjunctive cytokines was discussed. In addition, the difficulties of making decisions as to which of several alternative approaches was preferable, giving the fact that many of these antigens are found only in humans and therefore that animal models are either non-existent or artificial was discussed. The recent experience with the initial clinical trials using vaccines involving defined antigens was described.
The final two sessions of the meeting involved targeted approaches to immunobiological treatment. Dr. Nobuo Hanai described his company’s development of humanized antibodies against defined glycolipid antigens expressed on malignant melanoma, which form the basis for clinical trials soon to begin in Melbourne. These humanized antibodies were created from the murine antibodies which had originally been generated. Similar approaches are being used for the production of humanized antibodies against neuroblastoma. Dr. Hisataka Kobayashi who had been working with Dr. Keigo Endo of Gumma University and who is currently at the National Institutes of Health in Bethesda, described some of his experience with al humanized anti-TAC IgG monoclonal antibody in patients with T-cell malignancies. He showed clinical strategies designed to increase the effectiveness of radiolabelled antibody treatment strategies, including alteration of labeling methods, pre-targeting, and the use of an avidin chase in association with administration of biotinylated radiolabelled antibody.
Dr. Mansoor Saleh described other treatment monoclonal antibody-based-strategies in patients with a variety of malignancies, including non-Hodgkin’s lymphomas, ovarian cancer, and prostate cancer. He discussed a high-dose clinical trial in prostate cancer using lodine-131-iabeled anti-TAG-72 antibody, with autologous bone marrow transplantation support, and a similar trial also underway at the University of Alabama in breast cancer.
PARTICIPANTS
UNITED STATES
Dr. David Parkinson
Acting Associate Director
Cancer Therapy Evaluation Program
6130 Executive Boulevard, Room 742
Rockville, Maryland 20892-7438
Dr. Marty Sanda
University of Michigan Medical Center
1150 W. Medical Center Drive
Ann Arbor, Michigan 48109-0666
Dr. Patrick Geraghty
Research Fellow, Surgical Oncology Laboratory
University of Michigan Medical Center
1526, MSRB I
1150 W. Medical Center Drive
Ann Arbor. Michigan 48109-0666
Dr. Manoor Saleh
University of Alabama
Comprehensive Cancer Center
Tumor Institute 263, University Station
Birmingham, Alabama 35294
JAPAN
Dr. Makoto Ogawa
Aichi Cancer Center
Chikusa-ku, Nagoyashi 464
Dr. Arinobu Tojo
Tokyo University
Dr. Keigo Endo
Gumma University
Medical School
Maebashi, Gumma 371
Dr. Hisataka Kobayashi
National Institutes of Health
Dr. Kyogo Ito
Kurume University Medical School
Kurume-shi, Fukuoka 830
Dr. Nobuhiko Emi
Nagoya University
Dr. Yasufumi Kaneda
Osaka University Medical School
Suita-shi, Osaka 565
Dr. Emi Nobuhiko
Nagoya University School of Medicine
Chitane-ku, Nagoya-shi 461-01
(2) Seminar on “New Anticancer Drugs and Novel Hematopoietic Factors”
The focus of the Maui seminar February 12-13, 1996, was the discussion of promising new anticancer agents. Following introductory remarks by Drs. Ogawa and Parkinson, Dr. Yasufumi Sato presented a talk on the regulation of angiogenesis, and implications of this biology for novel clinical therapies. He described the drug irsogladine, which has been used for several years in Japan for the treatment of gastric ulcer and gastritis. He has found that this agent inhibits endothelial cell proliferation, and in vivo is an effective inhibitor of angiogenesis. In animal models, the agent inhibits the growth of solid tumors to a degree similar to that observed with the fumagillin analogs, anti-angiogenesis agents already in clinical trial. A randomized, controlled clinical trial of this agent given daily for 12 months in patients with diabetic retinopathy has recently shown a dramatic decrease in the formation of microaneurysms in patients receiving the drug. The potential use of this agent in the treatment of cancer, and the particular issues involved in clinical trial design and interpretation with the anti-angiogenesis class of agents was then the focus of discussion by the participants.
Dr. Nobuo Hanai then presented the developmental history of a series of anti-ganglioside monoclonal antibodies. He pointed out the potential advantages of tumor-associated cell surface gangliosides as targets for therapy, inasmuch as they tend to be highly expressed, there is relatively little heterogeneity of expression among tumor cells, and they are not down-regulated by antibody binding. Murine antibodies against GD3 (for melanoma), GM2 (for lung cancer therapy), and GD2 (for neuroblastoma therapy) have been developed, and chimeric and humanized antibodies created which recognized the same epitopes. Dr. Hanai described a phase I trial of the anti-melanoma antibody due to start in Melbourne, Australia, soon.
Dr. Nagahiro Saijo presented the preclinical data for NB 506, a new topoisomerase I inhibiting anticancer agent. The agent has additional mechanisms of action, and had proven quite active preclinically against murine tumors, and against human xenografts. He described the early results of a phase I clinical trial of NB5O6. He then described the initial clinical trial results of the initial Japanese phase I trial of spicamycin (KRN 5500), a novel agent developed by the Kirin Company. This presentation was of great interest since the U.S. National Cancer Institute was also initiating a phase I study of this agent.
Dr. David Parkinson presented a discussion of recent innovative approaches which the Investigational Drug Branch of the Cancer Therapy Evaluation Program had taken with respect to new agent phase I clinical development. He used a number of examples of new agents to discuss the particular developmental challenges posed by agents of different mechanisms of action.
Dr. Keisuke Aiba then described the general area of biochemical modulation of fluoropyrimidines as an anticancer treatment strategy. He described the use of S1, a combination of the oral fluorinated pyrimidine ftorafur, the DPD inhibitor CDHP, and oxonic acid, an inhibitor of 5-FU phosphorylation in the gastrointestinal tract. He described the considerable activity of S1, a drug developed by Taehoo Company, in gastric, colorectal, breast, and head and neck cancers.
Professor Takaku described Kirin 8602, a lipophilic anthracycline studied in a phase 11 study in patients with CNS tumors in Melbourne, Australia. Of 8 patients with glioblastoma, 2 were reported to have had a complete remission with treatment with this agent, whose major side effect is thrombocytopenia. He then described preclinical data on the agent KRN 7000, a novel antitumor alpha-galactosylceramide. This agent, derived from a marine sponge, has postulated immunostimulatory properties, and is a candidate for further clinical development.
Dr. Akihiro Shimosaka then described the structure, preclinical studies, and results of early clinical experience with the human platelet-stimulating agent, thrombopoietin. The particuiar thrombopoietin being brought into clinical trial by the Kirin Brewing Company together with Amgen is a pegylated form of the cytokine, termed rHuMGDF. Phase I trials of the agent have been completed and the ability of this novel hematopoietic factor to accelerate platelet recovery after intensive myelosuppressive chemotherapy is currently being studied in controlled clinical trials.
Dr. Takashi Tsuruo presented the results of his studies of apoptosis as a mechanism of anticancer agent activity, and of resistance to apoptosis as a mechanism of anti-tumor agent resistance. He presented evidence for the involvement of specific apoptotic pathways in the mechanism of resistance to VP-16.
Dr. Sabro Sone presented his preclinical studies concerning attempts to use gene therapy techniques to overcome chemotherapy-resistant tumors. He showed the results of transfection of mdr-resistant tumor cells with either the IL-2 or the M-CSF gene. He also discussed the potential use of the anti-mdr monoclonal antibody MRK16 in therapy of drug-resistant tumors.
Dr. Makoto Ogawa presented the results of clinical trials with Interleukin-3 in Japan. In phase I trials the dose-limiting toxicity of this cytokine was headache, and the agent appeared to shorten the period of serious thrombocytopenia. He then presented the results of a phase 11 clinical trial of IL-3 used together with G-CSF after combined carboplatin/etoposide chemotherapy f or small cell lung carcinoma, where he again concluded that the IL-3 shortened period of significant thrombocytopenia, and may also have affected the period of neutropenia expected with the low dose of G-CSF used. Dr. Debajit Biswas presented a discussion of the potential use of cytokine inhibitors in patients with AIDS or AIDS-related malignancies. Dr. Marcus Tius then discussed his work in the development of novel cytokine inhibitors, the kinds of agents which could be used for the treatment strategies suggested by Dr. Biswas’ studies.
PARTICIPANTS
UNITED STATES
Dr. Debajit Biswas
Dana Farber Cancer Institute
44 Binney Street Boston, Massachusetts 021 15
Dr. Marcus Tius
Department of Chemistry
University of Hawaii
2545 The Mall Honolulu, Hawaii 96822
Dr. David Parkinson
Acting Associate Director
Cancer Therapy Evaluation Program
6130 Executive Boulevard, MSC 7438
Rockville, Maryland 20892-7438
JAPAN
Dr. Takashi Tsuruo
Molecular and Cellular Biosciences
University of Tokyo
1-1-1, Yatoi-cho Bunkyo-ku Tokyo 113
Dr. Makoto Ogawa
Director, Aichi Cancer Center
1-1 Kamokoden Chikusa-ku
Nagoya 464
Dr. Keisuke Aiba
Cancer Chemotherapy Center
1-37-1 Kami-ikebukuro Toshima-ku
Tokyo 170
Dr. Nagahiro Saijo
National Cancer Center
5-1-1 Tsukiji Chuo-ku
Tokyo lO4
Dr. Fumimaro Takaku
National Medical Center
1-21-1 Toyama-cho
Shinjuku-ku
Tokyo 162
Dr. Yasufumi Sato
Institute of Aging and Cancer
Tohoku University
4-1 Seiyo-cho, Aoba-ku
Sendai 980-77
Dr. Sabro Sone
School of Medicine, Tokushima University
2-50-1 Kuramoto-cho, Tokushima 770
(3) Seminar on “New Approaches to the Treatment of Hematological Malignancies”
Following introductory remarks by Drs. Ogawa and Parkinson, the meeting on March 2-3, 1996, in Oakland, CA, began with a session discussing the use of all trans-retinoic acid (ATRA) in acute promyelocytic leukemia. Dr. Tomoki Naoe discussed the biology of the characteristic 15:17 reciprocal translocation found in this form of acute myelocytic leukemia, pointing out that the current evidence suggests that the PML-RARA protein suppresses normal cellular PML and RAR gene function in a dominant-negative method. The exact mechanism of this suppression, tlnd of its reversal by ATRA, have been unclear. Dr. Naoe presented evidence that exposure to ATRA accelerates degradation of the fusion protein, allowing restoration of both gene functions. He then presented some information regarding the development of retinoid resistance in APL, and the ability of a novel synthetic retinoid, AM-80, to reverse this resistance in vitro. He discussed dlso emerging inibrmation from China concerning the treatment of retinoid-refractory APL with As203, linking this with induction of apoptosis, and to differing subcellular localization of the PML-RAR alpha fusion protein.
Dr. Wilson Miller then presented the results of his studies in APL, He discussed the use of PCR techniques to predict the prognosis in APL patients induced to remission with ATRA, He then also discussed his own studies on the derived retinoid resistance of APL, which, similar to Dr. Naoe’s studies, also suggest that there is a cellular basis for resistance and that clinical resistance is not entirely due to the demonstrated pharmacological changes with continued ATRA administration, Dr. Miller then also discussed his work on the inhibition of breast cancer cell lines by ATRA, correlating the responsiveness of these lines with the presence of the estrogen receptor.
Dr. Akihisa Kanamaru described the results of a non-randomized multi-centered study (AML-92) using ATRA as a single agent in the induction therapy of patients with APL and low initial white cell counts, or together with daunorubicin and the cytosine arabinoside analog BHAC in patients with higher initial white counts. Some 298 patients were entered into this trial. which had an overall complete response rate of 89%.
Dr. Peter Wiernik presented the results of a study of patients with so-called variant M3 APL. These patients had a similar response rate to ATRA, He then presented the results of the NCI-sponsored Intergroup 0129 clinical trial, which was a trial involving more than 400 patients with newly-diagnosed APL who were treated with either ATRA or combination chemotherapy for initial treatment. All patients then received consolidation therapy with cytosinc arabinoside, and patients achieving complete response were randomized to maintenance therapy with ATRA or no additional therapy. There were no significant differences in response rates between the chemotherapy and ATRA, and no significant differences in early deaths. An important finding was that disease-free survival was better in all of the arms in which ATRA was administered.
Dr. Hideaki Mizoguchi then presented his data concerning the ability of stem cell factor (SCF) to mobilize peripheral blood stem cells, initially as a single agent in normal volunteers, and subsequently in combination with G-CSF. He described the characteristic adverse events associated with SCF therapy, including local induration, pruritus, and erythema.
Dr. Camille Abboud described the results of a randomized study of peripheral blood mobilization regimens in patients being treated with high dose chemotherapy and autologous transplantation in patients with breast cancer and lymphoma. He demonstrated also the results of preclinical studies involving the in vitro expansion of human CD34+ bone marrow progenitor cells.
Dr. Chihiro Shimazaki discussed the kinetics of appearance of total white blood cells, CD34 + cells, and CFU-GM after G-CSF mobilization. He also showed data suggesting that cell harvests were better after etoposide as compared with cyclophosphamide therapy, and data concerning the levels of G-CSF during neutropenia and subsequent neutrophil recovery. He described also recent studies of the Japan Blood Cell Transplantation Group, a group formed to answer questions regarding the use of cellular therapies in association with high-dose chemotherapy.
Dr. Masaharu Kasai presented a nationwide survey of the results of allogeneic peripheral blood cell stem cell transplantation (PBSCT) in Japan. Dr. John DiPersio then presented his own studies with allogeneic PBSCT. Potential advantages included the accelerated initial bone marrow recovery after myeloablative therapy, and apparent earlier immunological recovery with reduced risk of marrow rejection. Disadvantages include the fact that some donors have required placement of a central line, that the process requires that normal donors be treated with cytokines, and the increased risks of both graft-versus-host disease and cytomegalovirus infection. He also presented preclinical data involving new strategies in marrow transplantation.
Dr. Yoichi Takaue presented the results of autologous peripheral blood stem cells for pediatric leukemia patients. He showed examples of innovative ways in which young children could be apheresed.
Dr. Peter Ho discussed the general field of anti-sense treatment strategies as applied to hematological malignancies. He discussed technical considerations in anti-sense chemistry and the range of clinical targets that are being utilized in hematological malignancy therapy. Dr. Janice Dutcher concluded the presentations by summarizing the results of therapies with various biological agents in the hematological malignancies. She focused her remarks particularly on the use of cytokines either as single agents or in combination.
Dr. David Parkinson presented a summary of issues which had arisen in a recent FDA Advisory Committee meeting concerning peripheral blood cell transplantation. He discussed the issues of whether PBSCT would be regulated (only if they were considered to be manipulated), the potential definitions of manipulated cells, and the proposals for regulation of devices designed to manipulate these cells populations.
The meeting was characterized by active discussions, followed by suggestions for further studies. and possibilities for further research interactions among participants.
PARTICIPANTS
UNITED STATES
Dr. David Parkinson
Acting Associate Director
Cancer Therapy Evaluation Program
6130 Executive Boulevard, Room 742
Rockville, Maryland 20892
Dr. Peter Weirnik
Montefiore Medical Center
Oncology Department
111 E. 210th Street Bronx, New York 10467-2401
Dr. John DiPersio
Washington University
Division of Bone Marrow Transplantation
66 Southwest Euclid Avenue
St. Louis, Missouri 63110
Dr. Wilson Miller. Jr.
Lady Davis Institute for Medical Research
3775 Cote-Ste-Catherine
Montreal PQ, Canada H3U 1E2
Dr. Janice Dutcher
Montefiore Medical Center
Oncology Department
111 E. 210th Street
Bronx, New York 10467-2401
JA PAN
Dr. Hideaki Mizoguchi
Tokyo Women’s Medical College
Hiraga-cho 8-1 Shinjyuku
Tokyo 162
Tel: 03-3353-8111 Fax: 03-3353-8970
Dr. Makoto Ogawa
Director, Aichi Cancer Center
1-1 Kanokoden Chikusa-ku
Nagoya 464
Tel: 052-762-6111 Fax: 052-751-6948
Dr. Tomoki Naoe
Nagoya University School of Medicine
1-1-20 Daiko, Higashi-ku
Nagoya 461
Tel: 052-723-1111 Fax: 052-723-1118
Dr. Masaharu Kasai
Sapporo Hokuyu Hospital
6-6 Higashi Sapporo Shiroishi-ku
Sapporo 003
Tel: 011-83 2-0111 Fax: 011-865-9719
Dr. Akihisa Kanamaru
Hyogo College of Medicine
1-1 Mukogawa-cho, Nishinomiya-city
Hyogo 663
Tel: 0798-45-6592 Fax: 0798-45-6593
Dr. Chihiro Shimazaki
Kyoto Prefectural University of Medicine
465 Kawaramachi-Hirokji, Kamigyo-ku
Kyoto 602
Tel: 075-251-5511 Fax: 075-251-5514
Dr. Yoichi Takaue
University Hospital of Tokushima
Kuramoto-cho Tokushima 770
Tel: 0886-31-3111 Fax: 0886-31-8697