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Cancer Investigation, 8(2) 293-294 (1990)
Monoclonal Antibody Therapy in Intraabdominal Malignancies Franco M. Muggia Dimtor, Clinical Investigations Kenneth Norris Jr. Comprehensive Cancer Center Unlverslty of Southern California Los Angeles, California 90033
Thus, this radionuclide has powerful beta emission with a low total body exposure relative to 1311. As we approach this trial with optimismbased on these superior reagents, it is worth being reminded of some of the obstacles that may be faced in any MAb therapy. Obstacles to this overall strategy include:
The intraperitoneal (IF’) route has been shown to provide pharmacologic advantages for a number of IP administered drugs. Exploitation of such pharmacologic principles is taking place in ovarian cancer and beginning to evolve in gastrointestinal cancer after resection, particularly if the risk of peritoneal spread is identified. Beyond this high risk for peritoneal metastases, the rationale for use of IP therapy in these malignancies is related to the fact that (i) salvage systemic therapies are generally ineffective and (ii) that repeated intracavitary delivery has become feasible. In the case of monoclonal antibodies (MAb), the IP route represents an additionally useful delivery systemwith the potential of administering high doses to tumor-bearing areas, thus overcoming one obstacle to MAb treatment. On the other hand, immunologic reactions (i.e., human antimouse antibodies) are probably not diminished by the IP route. Clinical trials initially have utilized radiohmunmnjugates and more recently also immunotoxins. Prelhinary obseenatinsindicatepotential for useful antitumor effects. However, more specific antibodies, and radionuclides with more optimal characteristics are still being developed. We are embarking on a clinical trial with the NRX-451 MAb (from NmRx Corporation, Seattle) conjugated with Rhenium-186. It has a half-life of 3.7 days and a beta energy of 1070 with only 9% gamma energy.
1. Drug resistance: Gene amplification, extrachromosomalreplication, mutation or stepwise selection in fully or partly circumventing cytotoxicity (solution: modulation measures, better radionuclidcs). 2. Cellular heterogeneity: This factor is operative not only in immunologic but also in cytotoxic drug and in kinetic terms. Combined approaches, if anything, are more likely to overcome such obstacles and identifyhrget Goprecursors. 3. Pharrnacologics4mdume . s: In dditiolltotb centralnervoussystem, one must wnsider penetrance into tumors in relation to molecule size. (similar to problems of pewtrance after chemotherapy
administration). 4. Kinetic sanciuaries: These derive from variable antigenic expression during the cell cycle. 5 . Immwrologic barriers: These wuld occur through release of solu-
ble antigen following tumor destruction, and other factors blocking the action of antibodies.
In addition, general problems encountered in all IP approaches must be considered and are listed in Table 1. Nevertheless, the treatment of ovarian cancer illustrates how to launch a successful curative strategy through 293
294
Muggia TaMc 1 P o t d l Problems in IP &mpy
1. Insensitivity of tumor to agent used 2. Failure of distribution
3. Entry of patients unlikely to benefit 4. Miscellaaeous techaid problems and complications
suited for repeat treatment; criteria for tumor penetrance (molecular pharmacology)can be rigorously &find, immunologic interference may be minimized, while chemotherapeuticcytotoxicity cau be maximized through dose intensification, kinetic scheduling, and systemic neutralization. Similar approaches may be applicable to gastrointestinal cancers, which up to now have been refractory to systemic chemotherapy.
5. Misinterpretdon and/orinaccuracy of efficacy endpoints
Failure to explore other efficacy endpoints (markers, time to progression) 7. Uncritical adoption of regimens before optimization
Cancer Invest Downloaded from informahealthcare.com by Chulalongkorn University on 01/06/15 For personal use only.
6.
dbody-chemotherapy approaches: (i) surgicalresection, (ii) intracavitary therapy for early stages, (iii) systemic platinum-based chemotherapy, and (iv) intracavitary therapy for residual disease.Intracavitary therapy, a prototype of locoregional therapy, is especially suited for combined antibody and chemotherapy approaches: it is
REFERENCES 1 . Dedrick RL h s n e MF: Phammcokinetic Considcrationr on Monoclorrat' htibodies in ImmrCnty to h e r II. Allan Liss Inc., New York, 1989, pp 429-438. 2. Ballou B et al: Tumor location detected with radioactivity labeled monoclonal antibody and external scintigraphy. Science 206:844-847, 1979. 3. Eptmtos AA, MUIUOAJ et al: htibody-guided irradiationof advanced ovarian cancer with intraperitody administeredradiolabeled monoclonal antibodies. J Clin Oncol5:1890-1899, 1987. 4. Amstein NA, Wahl RL, Cochran M et al: Peritoneal distribution scintigraphy in patients with* ofthealimentarytract. Radiology 162:439-441, 1987.
Cancer Investigation, 8(2) 293-294 (1990)
Monoclonal Antibody Therapy in Intraabdominal Malignancies Franco M. Muggia Dimtor, Clinical Investigations Kenneth Norris Jr. Comprehensive Cancer Center Unlverslty of Southern California Los Angeles, California 90033
Thus, this radionuclide has powerful beta emission with a low total body exposure relative to 1311. As we approach this trial with optimismbased on these superior reagents, it is worth being reminded of some of the obstacles that may be faced in any MAb therapy. Obstacles to this overall strategy include:
The intraperitoneal (IF’) route has been shown to provide pharmacologic advantages for a number of IP administered drugs. Exploitation of such pharmacologic principles is taking place in ovarian cancer and beginning to evolve in gastrointestinal cancer after resection, particularly if the risk of peritoneal spread is identified. Beyond this high risk for peritoneal metastases, the rationale for use of IP therapy in these malignancies is related to the fact that (i) salvage systemic therapies are generally ineffective and (ii) that repeated intracavitary delivery has become feasible. In the case of monoclonal antibodies (MAb), the IP route represents an additionally useful delivery systemwith the potential of administering high doses to tumor-bearing areas, thus overcoming one obstacle to MAb treatment. On the other hand, immunologic reactions (i.e., human antimouse antibodies) are probably not diminished by the IP route. Clinical trials initially have utilized radiohmunmnjugates and more recently also immunotoxins. Prelhinary obseenatinsindicatepotential for useful antitumor effects. However, more specific antibodies, and radionuclides with more optimal characteristics are still being developed. We are embarking on a clinical trial with the NRX-451 MAb (from NmRx Corporation, Seattle) conjugated with Rhenium-186. It has a half-life of 3.7 days and a beta energy of 1070 with only 9% gamma energy.
1. Drug resistance: Gene amplification, extrachromosomalreplication, mutation or stepwise selection in fully or partly circumventing cytotoxicity (solution: modulation measures, better radionuclidcs). 2. Cellular heterogeneity: This factor is operative not only in immunologic but also in cytotoxic drug and in kinetic terms. Combined approaches, if anything, are more likely to overcome such obstacles and identifyhrget Goprecursors. 3. Pharrnacologics4mdume . s: In dditiolltotb centralnervoussystem, one must wnsider penetrance into tumors in relation to molecule size. (similar to problems of pewtrance after chemotherapy
administration). 4. Kinetic sanciuaries: These derive from variable antigenic expression during the cell cycle. 5 . Immwrologic barriers: These wuld occur through release of solu-
ble antigen following tumor destruction, and other factors blocking the action of antibodies.
In addition, general problems encountered in all IP approaches must be considered and are listed in Table 1. Nevertheless, the treatment of ovarian cancer illustrates how to launch a successful curative strategy through 293
294
Muggia TaMc 1 P o t d l Problems in IP &mpy
1. Insensitivity of tumor to agent used 2. Failure of distribution
3. Entry of patients unlikely to benefit 4. Miscellaaeous techaid problems and complications
suited for repeat treatment; criteria for tumor penetrance (molecular pharmacology)can be rigorously &find, immunologic interference may be minimized, while chemotherapeuticcytotoxicity cau be maximized through dose intensification, kinetic scheduling, and systemic neutralization. Similar approaches may be applicable to gastrointestinal cancers, which up to now have been refractory to systemic chemotherapy.
5. Misinterpretdon and/orinaccuracy of efficacy endpoints
Failure to explore other efficacy endpoints (markers, time to progression) 7. Uncritical adoption of regimens before optimization
Cancer Invest Downloaded from informahealthcare.com by Chulalongkorn University on 01/06/15 For personal use only.
6.
dbody-chemotherapy approaches: (i) surgicalresection, (ii) intracavitary therapy for early stages, (iii) systemic platinum-based chemotherapy, and (iv) intracavitary therapy for residual disease.Intracavitary therapy, a prototype of locoregional therapy, is especially suited for combined antibody and chemotherapy approaches: it is
REFERENCES 1 . Dedrick RL h s n e MF: Phammcokinetic Considcrationr on Monoclorrat' htibodies in ImmrCnty to h e r II. Allan Liss Inc., New York, 1989, pp 429-438. 2. Ballou B et al: Tumor location detected with radioactivity labeled monoclonal antibody and external scintigraphy. Science 206:844-847, 1979. 3. Eptmtos AA, MUIUOAJ et al: htibody-guided irradiationof advanced ovarian cancer with intraperitody administeredradiolabeled monoclonal antibodies. J Clin Oncol5:1890-1899, 1987. 4. Amstein NA, Wahl RL, Cochran M et al: Peritoneal distribution scintigraphy in patients with* ofthealimentarytract. Radiology 162:439-441, 1987.
