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Immunotherapeutic approaches to cancer control
lmmunotherapeutic approaches to cancer control Glenn A Warner, MD
In the field of oncology we are sensing an air of expectancy, in an atmosphere of hope which is replacing the unjustified and all too prevalent attitude of pessimism manifested by medical personnel and patients alike. The large amounts of money being spent on research are beginning to point the way toward cancer control. Every specialty contributing to cancer therapy is making significant contributions to better patient care.
Now we need to re-evaluate our approach to the treatment of malignant disease. Cancer, as we usually think of it, is the clinical phase of the disease process which becomes apGlenn A Warner, MD, i s a radiation oncologist a t the Tumor Institute of Swedish H o s p i t a l M e d i c a l Center, Seattle, Wash, a clinical assistant professor of radiology a t the University o f Washington M e d i c a l School, Seattle, and a member of t h e American College of Radiology. H e is a graduate of George Washington University M e d i c a l School, Washington, DC. D r W a r n e r has conducted several cancer research projects and has co-authored several papers on his work.
May 1973
parent when the tumor masses are large enough to cause symptoms or to be recognized on examinations. Studies of the growth patterns of tumors demonstrate that the growing tumor has been present months to years before it became clinically apparent. Circulating tumor cells can be recovered from the blood or in lymph nodes before the primary tumor has been diagnosed. In cancer of the cervix, abnormal cells can be demonstrated using Papanicolaou smears ten years before the tumor becomes invasive. In cancer surgery, x-ray therapy and chemotherapy give cures not because they remove all of the tumor but because they lower the tumor volume to a level that an immuno competent host can overcome the remaining tumor cells. Some observations may indicate the presence of a host immunity against tumors. Everson and Cole' recently documented over 200 cases of spontaneous
71
regression of proven cancer. After partial removal of a cancer by various methods of treatment, subsequent studies demonstrated disappearance of the remaining tumor, and the patient lived free of disease. Other surgeons have reported cases in which removal of the primary tumor mass has resulted in disappearance of metastatic nodules without additional treatment. Animal experiments have shown that a tumor transplanted or induced in an animal can be removed and, when an attempt is subsequently made to retransplant or re-induce that same tumor, the animal will reject it. Histologic studies of the area of rejection show large numbers of lymphocytes, macrophages, and ghosts of tumor cells. The pathologist examining cancer tissue removed by surgery always reports large infiltrates of lymphocytes in the tumor tissue because this indicates a more favorable prognosis for the patient. This is interpreted as an immunologic response on the part of the host against his cancer. Another example of possible host immunity against tumors is seen in those patients receiving organ transplants from donors with malignant disease. With the use of immunosuppressive measures to prevent the recipient from rejecting his graft, the malignant disease of the donor often develops in the recipient. Removal of the transplanted organ graft and withdrawal of the immunosuppressive agents result in regression of the induced tumor. Again sections demonstrate heavy lymphocyte infiltrate a t the site of tumor rejection. G ~ o d , and ~ , ~ others, have studied
72
the mechanism which enables the host to develop such immunologic protection. In studying people with immuno-deficient diseases, it was noted that those suffering from recurring infections were deficient in lymphocytes in certain areas of their lymph nodes. Other patients who had tumorogenic diseases, but good resistance against infections, were depleted of lymphocytes in other areas of their lymph nodes. In animal studies, removal of certain key organs produced immunologic deficiencies, reflecting two different immunologic defense mechanisms. One, called the thymic system, controls the cell mediated immunity against tumors. The other is the bursal system, which via plasma cell differentiation and production of immunoglobulins, protects against bacterial invaders. Removal of the thymus results in a depletion of lymphocytes in the paracortical areas of the lymph nodes and an inability of animals to reject grafts and tumors from unrelated donors. The bursal system’s controlling organ has not been fully localized in all mammals as yet. In chickens a localized pouch in the intestinal tract, called the Organ of Fabricius, is the center controlling the bursal system. In man this center seems to be localized in lymphoid masses in the tonsils, appendix, and Peyers Patches in the submucosa of the small intestine. However, removal of these known bursal centers results in lymphoid depletion in the germinal follicles of the lymph nodes and increased susceptibility to infections. These studies have established a mechanism by which host immunity can be promoted. Many different approaches to measure this host immunity are currently
AORN Journal
being used. Most notable, and gaining increasing acceptance, is the colonyinhibition tests developed by the Hell~ t r o m sThey . ~ first demonstrated that on the surface of every tumor cell there is an antigen which is peculiar to that particular tumor. Regardless of the individual in which the tumor develops, the surface antigenic marker is the same and can be identified in all tumors of the same type. Tumors can be grown in tissue culture and, when lymphocytes from patients with that particular tumor are added to the culture system, destruction or inhibition of colonies of growing tumor cells results. The amount of colony inhibition relates directly to the patient’s ability to destroy his tumor and is termed the cell mediated immunity (CMI) . If serum from the blood of patients with growing tumor is added to this system, the lymphocytes’ destruction of the colonies of tumor cells is blocked. Sjorgren5 has show us that this so-called blocking antibody is a complex of tumor antigen and antibody produced by the patient against his tumor. The blocking antibody (BAb) attaches itself to the receptor sites on the thymic lymphocytes sensitized against the tumor, preventing them from attacking the tumor cells.
In those patients who have successfully controlled their cancers, and in those from whom sufficient tumor mass is removed, another antibody is produced by the host which destroys the blocking antibody. This is the unblocking antibody present in the patient’s serum and is another means by which host immunity against tumor is mediated. Addition of this unblocking antibody serum to a system containing tumor cells, patient’s
Mtry 197’::
lymphocytes, and blocking antibodies will result in release of lymphocytes to attack the tumor cells. Measurement of these immune factors correlates directly with the clinical state in the patient. If the cell mediated immunity is high, he is fighting his tumor. When tumor is actively growing and gaining control over the host, the blocking antibody titer is high and rising. Successful control of the tumor results in the appearance of the unblocking antibody and a rising cell mediated immunity. Using these measurements, we are treating patients with malignant disease by first trying to raise the cell mediated immunity. LymphocytG stimulation currently is mainly by means of BCG vaccine scarified on the skin and occasionally with intralesional injections. Challenging the host immune mechanisms through skin injections is a time honored way of improving immunity against foreign invaders. Other non-specific lymphocyte stimulants used are dinitrochlorbenzene (DNCB) , and other bacterial vaccines. There are several other substances which will soon be available for use.
To lower the blocking antibody titer we have been able to reduce tumor volume, using plasma obtained from patients who have successfully handled their tumors. Using the colony inhibition tests, it has been demonstrated by t h e Hellstroms,6J Morton, and others that plasma of relatives of patients with tumor can be used in some instances to destroy the blocking antibody. Certain ethnic groups with heavily pigmented skin have, over many generations, developed a protective antibody against
73
the development of malignant melanoma, a particularly vicious cancer arising in light skinned races, usually from pre-existing pigmented moles. Plasma from these more favored races has destroyed malignant melanoma in patients with this particular tumor. There are several other approaches that our colleagues in basic sciences are developing which will be of value in the immediate future in reducing the blocking antibody titers. Using these procedures, clinical experience is being gained in treatment of neuroblastoma, melanomas, kidney cancers, and osteogenic sarcomas. Objective evidence of response is available but exact treatment methods are still being developed. Just as everything else in medicine, immunotherapy is a two edged sword and improper use will favor the growth of the tumor over host immune mechanism. Studies must be well controlled and constantly evaluated to prevent harm to the patient. At this time, I feel immunotherapy promises to be a valuable adjuvant to cancer therapy. Tumor masses will regress with its use. The lower the tumor volume, the more effective host immunity will become. This may indicate a need for more frequent, but less aggressive, surgical procedures. The same applies to x-ray therapy, with different dose rates. Chemotherapists should think more about undue suppression of the host immune mechanism rather than concen-
trating on total tumor destruction by prolonged, aggressive drug therapy. Preliminary stimulation of the immune mechanisms, prior to any therapy, will reduce the secondary immuno-suppression which occurs with standard therapeutic approaches. This also will allow enhancement of host response at an earlier date and aid in controlling portions of tumor remaining. Hopefully, continued studies will justify this pathophysiologic approach t o cancer therapy and allow better control of this dread disease. REFERENCES I. T C Everson and W H Cole, Spontaneous Regression of Cancer (Philadelphia: Saunders, 1966). 2. R A Good and J Finstad, "Essential relationship between the lymphoid system and malignancy," Journal of the National Cancer Institute, monograph 31, 1969, p41.
3. J W Alexander and R A Good, Immunobiology for Surgeons (.Philadelphia: Saunders, 1970). 4. I Hellstrom and K E Hellstrom, "Cellular Immunity against tumor antigens," Advances in Cancer Research, 12 (1969) 167.
5. H 0 Sjogren, et al, Suggestive Evidence that the blocking antibodies of tumor-bearing individuals may be antigen-antibody complexes, proceedings, National Academy of Science, USA, 68 (19711, 1372. 6. I Hellstrom, e t al, "Sequential studies on cellmediated tumor immunity and blocking serum activity in ten patients with Malignant Melanoma," Internotional Journal of Cancer, i n press, 1973.
7.
D L
Morton, e t al, "Demonstration of anti-
bodies against human malignant melanomas by immunofluorescence," Surgery, 64 ( l968), 233.
Infanfs suffer h e a d affacks The first documented cases o f infants dying o f heart attack with widespread hardening of the arteries has been reported in Circulation. Helmar G Rosenberg, MD, reported that two unrelated two-year-old boys from Antofagasta, Chile, died of heart attacks with generalized, widespread arteriosclerosis. H e said the disease in the infants may be related t o poisoning from drinking water with high levels of arsenic found in their area.
74
AORN Joumal
In the field of oncology we are sensing an air of expectancy, in an atmosphere of hope which is replacing the unjustified and all too prevalent attitude of pessimism manifested by medical personnel and patients alike. The large amounts of money being spent on research are beginning to point the way toward cancer control. Every specialty contributing to cancer therapy is making significant contributions to better patient care.
Now we need to re-evaluate our approach to the treatment of malignant disease. Cancer, as we usually think of it, is the clinical phase of the disease process which becomes apGlenn A Warner, MD, i s a radiation oncologist a t the Tumor Institute of Swedish H o s p i t a l M e d i c a l Center, Seattle, Wash, a clinical assistant professor of radiology a t the University o f Washington M e d i c a l School, Seattle, and a member of t h e American College of Radiology. H e is a graduate of George Washington University M e d i c a l School, Washington, DC. D r W a r n e r has conducted several cancer research projects and has co-authored several papers on his work.
May 1973
parent when the tumor masses are large enough to cause symptoms or to be recognized on examinations. Studies of the growth patterns of tumors demonstrate that the growing tumor has been present months to years before it became clinically apparent. Circulating tumor cells can be recovered from the blood or in lymph nodes before the primary tumor has been diagnosed. In cancer of the cervix, abnormal cells can be demonstrated using Papanicolaou smears ten years before the tumor becomes invasive. In cancer surgery, x-ray therapy and chemotherapy give cures not because they remove all of the tumor but because they lower the tumor volume to a level that an immuno competent host can overcome the remaining tumor cells. Some observations may indicate the presence of a host immunity against tumors. Everson and Cole' recently documented over 200 cases of spontaneous
71
regression of proven cancer. After partial removal of a cancer by various methods of treatment, subsequent studies demonstrated disappearance of the remaining tumor, and the patient lived free of disease. Other surgeons have reported cases in which removal of the primary tumor mass has resulted in disappearance of metastatic nodules without additional treatment. Animal experiments have shown that a tumor transplanted or induced in an animal can be removed and, when an attempt is subsequently made to retransplant or re-induce that same tumor, the animal will reject it. Histologic studies of the area of rejection show large numbers of lymphocytes, macrophages, and ghosts of tumor cells. The pathologist examining cancer tissue removed by surgery always reports large infiltrates of lymphocytes in the tumor tissue because this indicates a more favorable prognosis for the patient. This is interpreted as an immunologic response on the part of the host against his cancer. Another example of possible host immunity against tumors is seen in those patients receiving organ transplants from donors with malignant disease. With the use of immunosuppressive measures to prevent the recipient from rejecting his graft, the malignant disease of the donor often develops in the recipient. Removal of the transplanted organ graft and withdrawal of the immunosuppressive agents result in regression of the induced tumor. Again sections demonstrate heavy lymphocyte infiltrate a t the site of tumor rejection. G ~ o d , and ~ , ~ others, have studied
72
the mechanism which enables the host to develop such immunologic protection. In studying people with immuno-deficient diseases, it was noted that those suffering from recurring infections were deficient in lymphocytes in certain areas of their lymph nodes. Other patients who had tumorogenic diseases, but good resistance against infections, were depleted of lymphocytes in other areas of their lymph nodes. In animal studies, removal of certain key organs produced immunologic deficiencies, reflecting two different immunologic defense mechanisms. One, called the thymic system, controls the cell mediated immunity against tumors. The other is the bursal system, which via plasma cell differentiation and production of immunoglobulins, protects against bacterial invaders. Removal of the thymus results in a depletion of lymphocytes in the paracortical areas of the lymph nodes and an inability of animals to reject grafts and tumors from unrelated donors. The bursal system’s controlling organ has not been fully localized in all mammals as yet. In chickens a localized pouch in the intestinal tract, called the Organ of Fabricius, is the center controlling the bursal system. In man this center seems to be localized in lymphoid masses in the tonsils, appendix, and Peyers Patches in the submucosa of the small intestine. However, removal of these known bursal centers results in lymphoid depletion in the germinal follicles of the lymph nodes and increased susceptibility to infections. These studies have established a mechanism by which host immunity can be promoted. Many different approaches to measure this host immunity are currently
AORN Journal
being used. Most notable, and gaining increasing acceptance, is the colonyinhibition tests developed by the Hell~ t r o m sThey . ~ first demonstrated that on the surface of every tumor cell there is an antigen which is peculiar to that particular tumor. Regardless of the individual in which the tumor develops, the surface antigenic marker is the same and can be identified in all tumors of the same type. Tumors can be grown in tissue culture and, when lymphocytes from patients with that particular tumor are added to the culture system, destruction or inhibition of colonies of growing tumor cells results. The amount of colony inhibition relates directly to the patient’s ability to destroy his tumor and is termed the cell mediated immunity (CMI) . If serum from the blood of patients with growing tumor is added to this system, the lymphocytes’ destruction of the colonies of tumor cells is blocked. Sjorgren5 has show us that this so-called blocking antibody is a complex of tumor antigen and antibody produced by the patient against his tumor. The blocking antibody (BAb) attaches itself to the receptor sites on the thymic lymphocytes sensitized against the tumor, preventing them from attacking the tumor cells.
In those patients who have successfully controlled their cancers, and in those from whom sufficient tumor mass is removed, another antibody is produced by the host which destroys the blocking antibody. This is the unblocking antibody present in the patient’s serum and is another means by which host immunity against tumor is mediated. Addition of this unblocking antibody serum to a system containing tumor cells, patient’s
Mtry 197’::
lymphocytes, and blocking antibodies will result in release of lymphocytes to attack the tumor cells. Measurement of these immune factors correlates directly with the clinical state in the patient. If the cell mediated immunity is high, he is fighting his tumor. When tumor is actively growing and gaining control over the host, the blocking antibody titer is high and rising. Successful control of the tumor results in the appearance of the unblocking antibody and a rising cell mediated immunity. Using these measurements, we are treating patients with malignant disease by first trying to raise the cell mediated immunity. LymphocytG stimulation currently is mainly by means of BCG vaccine scarified on the skin and occasionally with intralesional injections. Challenging the host immune mechanisms through skin injections is a time honored way of improving immunity against foreign invaders. Other non-specific lymphocyte stimulants used are dinitrochlorbenzene (DNCB) , and other bacterial vaccines. There are several other substances which will soon be available for use.
To lower the blocking antibody titer we have been able to reduce tumor volume, using plasma obtained from patients who have successfully handled their tumors. Using the colony inhibition tests, it has been demonstrated by t h e Hellstroms,6J Morton, and others that plasma of relatives of patients with tumor can be used in some instances to destroy the blocking antibody. Certain ethnic groups with heavily pigmented skin have, over many generations, developed a protective antibody against
73
the development of malignant melanoma, a particularly vicious cancer arising in light skinned races, usually from pre-existing pigmented moles. Plasma from these more favored races has destroyed malignant melanoma in patients with this particular tumor. There are several other approaches that our colleagues in basic sciences are developing which will be of value in the immediate future in reducing the blocking antibody titers. Using these procedures, clinical experience is being gained in treatment of neuroblastoma, melanomas, kidney cancers, and osteogenic sarcomas. Objective evidence of response is available but exact treatment methods are still being developed. Just as everything else in medicine, immunotherapy is a two edged sword and improper use will favor the growth of the tumor over host immune mechanism. Studies must be well controlled and constantly evaluated to prevent harm to the patient. At this time, I feel immunotherapy promises to be a valuable adjuvant to cancer therapy. Tumor masses will regress with its use. The lower the tumor volume, the more effective host immunity will become. This may indicate a need for more frequent, but less aggressive, surgical procedures. The same applies to x-ray therapy, with different dose rates. Chemotherapists should think more about undue suppression of the host immune mechanism rather than concen-
trating on total tumor destruction by prolonged, aggressive drug therapy. Preliminary stimulation of the immune mechanisms, prior to any therapy, will reduce the secondary immuno-suppression which occurs with standard therapeutic approaches. This also will allow enhancement of host response at an earlier date and aid in controlling portions of tumor remaining. Hopefully, continued studies will justify this pathophysiologic approach t o cancer therapy and allow better control of this dread disease. REFERENCES I. T C Everson and W H Cole, Spontaneous Regression of Cancer (Philadelphia: Saunders, 1966). 2. R A Good and J Finstad, "Essential relationship between the lymphoid system and malignancy," Journal of the National Cancer Institute, monograph 31, 1969, p41.
3. J W Alexander and R A Good, Immunobiology for Surgeons (.Philadelphia: Saunders, 1970). 4. I Hellstrom and K E Hellstrom, "Cellular Immunity against tumor antigens," Advances in Cancer Research, 12 (1969) 167.
5. H 0 Sjogren, et al, Suggestive Evidence that the blocking antibodies of tumor-bearing individuals may be antigen-antibody complexes, proceedings, National Academy of Science, USA, 68 (19711, 1372. 6. I Hellstrom, e t al, "Sequential studies on cellmediated tumor immunity and blocking serum activity in ten patients with Malignant Melanoma," Internotional Journal of Cancer, i n press, 1973.
7.
D L
Morton, e t al, "Demonstration of anti-
bodies against human malignant melanomas by immunofluorescence," Surgery, 64 ( l968), 233.
Infanfs suffer h e a d affacks The first documented cases o f infants dying o f heart attack with widespread hardening of the arteries has been reported in Circulation. Helmar G Rosenberg, MD, reported that two unrelated two-year-old boys from Antofagasta, Chile, died of heart attacks with generalized, widespread arteriosclerosis. H e said the disease in the infants may be related t o poisoning from drinking water with high levels of arsenic found in their area.
74
AORN Joumal