Nucl. Med. Biol. Vol. 18, No. I, pp. l-2, 1991 h. J. Radiat. Appl. hstrum. Part B
0883-2897191 $3.00 + 0.00
Pergamon Press
plc
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INTRODUCTION
Second International Conference on Diagnosis and Therapy with Monoclonal Antibodies The theme of this conference was the use of special antibodies, which react with human tumors, as carriers for radioactive elements useful in diagnosis and treatment using nuclear medicine techniques. An international organizing committee, composed of experts from Europe and the U.S.A., prepared a program which included top scientists working in this field. The recent progress in this area of cancer research, is based on certain advances in basic immunology and radiotracer chemistry. Special immune proteins which react with marker proteins and other unique components of tumor cells are created by specialized laboratory techniques, and these tumor specific antibodies are labeled with radioactive elements in a delicate micro-chemistry, so that the fragile anti-tumor antibodies are not damaged. After appropriate purification, the radiolabeled antibodies are injected intravenously into patients with cancer. Clinical experience has shown that tumors which would be otherwise hidden, can be diagnosed with nuclear medicine imaging techniques (also called radioimmunodiagnosis). With progressive refinement in treatment strategies, selected cases of human tumors including lymphomas, leukemias and the padiatric tumor, neuroblastoma, have responded to therapeutic amounts of these radiolabeled antibodies. (The technique is called radioimmunotherapy.) Dr Jeffrey Schlom, of the National Cancer Institute, U.S.A., discussed his pioneering work whereby certain anti-tumor antibodies against human adenocarcinomas-breast, ovary, lung and colon cancer-have been progressively refined by incremental improvements in selection of antibodies and radiochemistry. Recent work reported from Dr Schlom’s laboratory at this conference, described second and third generation antibodies which have increased tumor seeking abilities; appropriate curative regimes of radiommunotherapy in experimental animals; genetic engineering techniques to create “single chain” antigen reactive peptides; and the role of stimulating biologic modifiers such as interferon, in increasing the amount of tumor marker substances which radioantibodies can target to in the living patient. In describing nearly a decade of work, Dr Schlom’s efforts can be seen as a scientific paradigm, for intelligent exploitation of advances in biotechnology to improve the diagnosis and therapy of human cancer. Dr William Eckelman described some of the advances in radiochemistry, which make it likely that technetium-99m will be more and more widely used in radioimmunodiagnosis of human tumors. The recent development of simple and reliable labeling strategies for %Tc, promises to make these methods available to many laboratories, not only in Europe and the U.S.A., but also throughout the developing countries of the world. Radiochemistry advances have added greatly to potential for both diagnosis and therapy with the radiolabel “tailored” to match a specific tumor type and patient population. Dr Otto Gansow, of the National Cancer Institute, an expert on radiometal chelation to antibodies and Dr Ronald Finn, of Memorial Sloan-Kettering Cancer Center, an expert on radioisotope production with cyclotrons, presented state-of-the-art lectures on optimal radioantibody labeling conditions for the radionuclides “‘In, “Y, as well as the positron emitters 66Ga and lz41. The methods described by these leaders in the chemistry of radiopharmaceutical production promise improved clinical products for both radioimmunodiagnosis and radioimmunotherapy in the near future. Significant clinical progress which was described in this conference included the detection of previously unsuspected tumor spread from primary sites in the colon to secondary sites in the liver. Also, tumor shrinkage was noted with radioimmunotherapy of certain treatment resistant tumors of colon, ovary, breast, neuroblastoma and lymphoma origin. These findings were based on certain unique and very promising antibodies against human tumors. The most widely studied of these antibodies was B72.3, an anti-colon cancer antibody produced in Dr Schlom’s laboratory which has been injected into over 2000 patients, worldwide. Other antibodies which appear to have unusually specific targeting for clinical purposes include the 3F8 antibody against a specific tumor marker in neuroblastoma (discovered by Cheung et al., Memorial Sloan-Kettering Cancer Center); an anti-colon antibody radiolabeled with 99mTc, PR103 (Britton et al., London, U.K.); anti-CEA antibodies labeled with ‘*‘I (Bischoff-Delaloye, Lausanne, Switzerland), and “‘In (Abbott Laboratories, Chicago, Ill., U.S.A.), and 13iI LYM-1 (De Nardo et al., Sacramento, Calif., U.S.A.). 1
2
Introduction
The contributions of the Italians in this field have been considerable. For example, the first comprehensive multi-center clinical trials on anti-CEA antibodies in colon cancer were performed by a cooperative Italian group (reviewed by M. Gasparini, Milan). Conclusive evidence was presented to show that patients previously thought to be without disease were found to have occult tumor, and in some cases this discovery had the potential to be life-saving, in that early therapy could be instituted. In addition, Dr Pietro Riva (Cesena, Italy) reported very encouraging results in the therapy of gastrointestinal cancer after intraperitoneal injection of radiolabeled B72.3 (I” I). An important aspect of this study was that in addition to both partial and complete therapeutic responses in a minority of patients, a significant proportion of otherwise untreatable patients with advanced cancer experienced improvement in quality of life after therapy, with reduction in pain and improvement in ability to carry out the normal activities of life. Depending in part on the tumor marker which is its antigen target, anti-tumor antibodies may be bound in uivo to the external cell surface or subsequent to external binding may be transported into the interior of the tumor cell in a kind of microscopic swallowing maneuver. Dr Luther Brady of Philadelphia, reported that complete responses had been observed in a minority of patients with advanced primary brain tumors and colorectal carcinoma when these patients are treated with radiolabeled antibodies that are taken up by tumor cells into the region of the nucleus. These antibodies, provided by the Wistar Institute scientists, were labeled with’251, and antibody with very powerful but short-range radiations. The clinical study was inspired in part by the elegant basic radiobiology studies of Dr James Adelstein of Harvard (Boston, Mass., U.S.A.), who described the potent killing potential and the underlying biology of agents which can be incorporated directly into DNA. 12’1,and other radioisotopes that undergo decay by a type of radioactivity called electron capture decay, are particularly well suited for destroying cancer cells from within if bound to the DNA structure. Dr Adelstein’s conceptual framework included a proposal, for linking internalized anti-tumor antibodies with ‘25I in the form of iododeoxyuridine; a chemical structure which is readily incorporated into the most radiosensitive portion of the DNA within the nucleus of a cell. If successful, such methods would greatly increase the tumor killing power of the radiolabeled antibody, while sparing the normal radiosensitive tissue of toxic levels of radiation. Perhaps the most significant new report at this conference was related to a preliminary finding of a response in a patient with advanced breast cancer, when treated with radioimmunotherapy with 13’I L-6. In this report, a patient with cutaneous involvement of the chest wall with breast cancer received considerable benefit from treatment from radiolabeled “humanized” (chime&) L-6 antibody, co-administered with L-6 of mouse protein origin. If additional studies give similar results in a larger group of patients, this approach represents a significant therapeutic advance in an important subset of patients with cancer of the breast who have local recurrence of their cancer in the chest wall after removal of the primary cancer. (S. De Nardo, Sacramento, Cahf., U.S.A.). In summary, this conference set an optimistic tone, even while dealing with some of the biologic difficulties and uncertainties of targeting of radiolabeled antibodies to sequestered antigen deposits on tumors in living patients. Problems remain to be overcome and for some tumor systems inadequate antigen expression or slow diffusion of radiolabeled antibody into the tumor region limit practical applications. In addition to improved radiolabeling methods, technical improvements in imaging methods such as combined use of conventional x-ray CT and SPECT methods in a computerized “fusion” technique, will make image interpretation more objective (E. Kramer, New York). In addition, many new and promising antibodies are just entering clinical trials for both leukemia/lymphoma antibodies (such as the M-195 anti-leukemia antibody described by Schienberg, New York), and solid tumors such as A-33, a colon cancer antibody introduced by Welt, Divgi and Old (New York). These new antibody preparations promise benefits for both diagnosis and therapy. Furthermore, as greater knowledge develops regarding the nature of the marker protein target on tumor cells, in some cases, such as the anti-EGF antibodies developed by Mendelsohn and Koprowski, uptake of the radiolabeled antibody in viuo provides biological characteristics of the tumor which may have implications for prognosis or therapy. Finally, it is also clear that by patient application of recent advances in biotechnology, excellent radiolabeled antibodies have resulted and the assembled experts noted specific examples of positive results in clinical trials. The potential of this methodology remains broad, and in the near future, it is likely that improved diagnosis and therapy will result for some of the most common and treatment resistant of human cancers. STEVENM. LARSON Memorial Sloan-Kettering Cancer Center New York NY 10021, U.S.A.
0883-2897191 $3.00 + 0.00
Pergamon Press
plc
Printed in Great Britain
INTRODUCTION
Second International Conference on Diagnosis and Therapy with Monoclonal Antibodies The theme of this conference was the use of special antibodies, which react with human tumors, as carriers for radioactive elements useful in diagnosis and treatment using nuclear medicine techniques. An international organizing committee, composed of experts from Europe and the U.S.A., prepared a program which included top scientists working in this field. The recent progress in this area of cancer research, is based on certain advances in basic immunology and radiotracer chemistry. Special immune proteins which react with marker proteins and other unique components of tumor cells are created by specialized laboratory techniques, and these tumor specific antibodies are labeled with radioactive elements in a delicate micro-chemistry, so that the fragile anti-tumor antibodies are not damaged. After appropriate purification, the radiolabeled antibodies are injected intravenously into patients with cancer. Clinical experience has shown that tumors which would be otherwise hidden, can be diagnosed with nuclear medicine imaging techniques (also called radioimmunodiagnosis). With progressive refinement in treatment strategies, selected cases of human tumors including lymphomas, leukemias and the padiatric tumor, neuroblastoma, have responded to therapeutic amounts of these radiolabeled antibodies. (The technique is called radioimmunotherapy.) Dr Jeffrey Schlom, of the National Cancer Institute, U.S.A., discussed his pioneering work whereby certain anti-tumor antibodies against human adenocarcinomas-breast, ovary, lung and colon cancer-have been progressively refined by incremental improvements in selection of antibodies and radiochemistry. Recent work reported from Dr Schlom’s laboratory at this conference, described second and third generation antibodies which have increased tumor seeking abilities; appropriate curative regimes of radiommunotherapy in experimental animals; genetic engineering techniques to create “single chain” antigen reactive peptides; and the role of stimulating biologic modifiers such as interferon, in increasing the amount of tumor marker substances which radioantibodies can target to in the living patient. In describing nearly a decade of work, Dr Schlom’s efforts can be seen as a scientific paradigm, for intelligent exploitation of advances in biotechnology to improve the diagnosis and therapy of human cancer. Dr William Eckelman described some of the advances in radiochemistry, which make it likely that technetium-99m will be more and more widely used in radioimmunodiagnosis of human tumors. The recent development of simple and reliable labeling strategies for %Tc, promises to make these methods available to many laboratories, not only in Europe and the U.S.A., but also throughout the developing countries of the world. Radiochemistry advances have added greatly to potential for both diagnosis and therapy with the radiolabel “tailored” to match a specific tumor type and patient population. Dr Otto Gansow, of the National Cancer Institute, an expert on radiometal chelation to antibodies and Dr Ronald Finn, of Memorial Sloan-Kettering Cancer Center, an expert on radioisotope production with cyclotrons, presented state-of-the-art lectures on optimal radioantibody labeling conditions for the radionuclides “‘In, “Y, as well as the positron emitters 66Ga and lz41. The methods described by these leaders in the chemistry of radiopharmaceutical production promise improved clinical products for both radioimmunodiagnosis and radioimmunotherapy in the near future. Significant clinical progress which was described in this conference included the detection of previously unsuspected tumor spread from primary sites in the colon to secondary sites in the liver. Also, tumor shrinkage was noted with radioimmunotherapy of certain treatment resistant tumors of colon, ovary, breast, neuroblastoma and lymphoma origin. These findings were based on certain unique and very promising antibodies against human tumors. The most widely studied of these antibodies was B72.3, an anti-colon cancer antibody produced in Dr Schlom’s laboratory which has been injected into over 2000 patients, worldwide. Other antibodies which appear to have unusually specific targeting for clinical purposes include the 3F8 antibody against a specific tumor marker in neuroblastoma (discovered by Cheung et al., Memorial Sloan-Kettering Cancer Center); an anti-colon antibody radiolabeled with 99mTc, PR103 (Britton et al., London, U.K.); anti-CEA antibodies labeled with ‘*‘I (Bischoff-Delaloye, Lausanne, Switzerland), and “‘In (Abbott Laboratories, Chicago, Ill., U.S.A.), and 13iI LYM-1 (De Nardo et al., Sacramento, Calif., U.S.A.). 1
2
Introduction
The contributions of the Italians in this field have been considerable. For example, the first comprehensive multi-center clinical trials on anti-CEA antibodies in colon cancer were performed by a cooperative Italian group (reviewed by M. Gasparini, Milan). Conclusive evidence was presented to show that patients previously thought to be without disease were found to have occult tumor, and in some cases this discovery had the potential to be life-saving, in that early therapy could be instituted. In addition, Dr Pietro Riva (Cesena, Italy) reported very encouraging results in the therapy of gastrointestinal cancer after intraperitoneal injection of radiolabeled B72.3 (I” I). An important aspect of this study was that in addition to both partial and complete therapeutic responses in a minority of patients, a significant proportion of otherwise untreatable patients with advanced cancer experienced improvement in quality of life after therapy, with reduction in pain and improvement in ability to carry out the normal activities of life. Depending in part on the tumor marker which is its antigen target, anti-tumor antibodies may be bound in uivo to the external cell surface or subsequent to external binding may be transported into the interior of the tumor cell in a kind of microscopic swallowing maneuver. Dr Luther Brady of Philadelphia, reported that complete responses had been observed in a minority of patients with advanced primary brain tumors and colorectal carcinoma when these patients are treated with radiolabeled antibodies that are taken up by tumor cells into the region of the nucleus. These antibodies, provided by the Wistar Institute scientists, were labeled with’251, and antibody with very powerful but short-range radiations. The clinical study was inspired in part by the elegant basic radiobiology studies of Dr James Adelstein of Harvard (Boston, Mass., U.S.A.), who described the potent killing potential and the underlying biology of agents which can be incorporated directly into DNA. 12’1,and other radioisotopes that undergo decay by a type of radioactivity called electron capture decay, are particularly well suited for destroying cancer cells from within if bound to the DNA structure. Dr Adelstein’s conceptual framework included a proposal, for linking internalized anti-tumor antibodies with ‘25I in the form of iododeoxyuridine; a chemical structure which is readily incorporated into the most radiosensitive portion of the DNA within the nucleus of a cell. If successful, such methods would greatly increase the tumor killing power of the radiolabeled antibody, while sparing the normal radiosensitive tissue of toxic levels of radiation. Perhaps the most significant new report at this conference was related to a preliminary finding of a response in a patient with advanced breast cancer, when treated with radioimmunotherapy with 13’I L-6. In this report, a patient with cutaneous involvement of the chest wall with breast cancer received considerable benefit from treatment from radiolabeled “humanized” (chime&) L-6 antibody, co-administered with L-6 of mouse protein origin. If additional studies give similar results in a larger group of patients, this approach represents a significant therapeutic advance in an important subset of patients with cancer of the breast who have local recurrence of their cancer in the chest wall after removal of the primary cancer. (S. De Nardo, Sacramento, Cahf., U.S.A.). In summary, this conference set an optimistic tone, even while dealing with some of the biologic difficulties and uncertainties of targeting of radiolabeled antibodies to sequestered antigen deposits on tumors in living patients. Problems remain to be overcome and for some tumor systems inadequate antigen expression or slow diffusion of radiolabeled antibody into the tumor region limit practical applications. In addition to improved radiolabeling methods, technical improvements in imaging methods such as combined use of conventional x-ray CT and SPECT methods in a computerized “fusion” technique, will make image interpretation more objective (E. Kramer, New York). In addition, many new and promising antibodies are just entering clinical trials for both leukemia/lymphoma antibodies (such as the M-195 anti-leukemia antibody described by Schienberg, New York), and solid tumors such as A-33, a colon cancer antibody introduced by Welt, Divgi and Old (New York). These new antibody preparations promise benefits for both diagnosis and therapy. Furthermore, as greater knowledge develops regarding the nature of the marker protein target on tumor cells, in some cases, such as the anti-EGF antibodies developed by Mendelsohn and Koprowski, uptake of the radiolabeled antibody in viuo provides biological characteristics of the tumor which may have implications for prognosis or therapy. Finally, it is also clear that by patient application of recent advances in biotechnology, excellent radiolabeled antibodies have resulted and the assembled experts noted specific examples of positive results in clinical trials. The potential of this methodology remains broad, and in the near future, it is likely that improved diagnosis and therapy will result for some of the most common and treatment resistant of human cancers. STEVENM. LARSON Memorial Sloan-Kettering Cancer Center New York NY 10021, U.S.A.
