Clinical experience with transfer and direct turhor-specific immunity in the treatment of 24 advanced cancer patients with observations on "post surgical" immunoprophylaxis and local immunotherapy

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Part of The Journal of the Philippine Medical Association

Title: Clinical experience with transfer and direct turhor-specific immunity in the treatment of 24 advanced cancer patients with observations on "post surgical" immunoprophylaxis and local immunotherapy
Creator: Gomez, Rodney A.
Language: English
Source: The Journal of the Philippine Medical Association Volume 52 (Issue Nos. 9-10) September-October 1976
Year: 1976
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Fulltext: Clinical Experience with Transfer and Direct Tumor-Specific Immunity in the Treatment of 24 Advanced Cancer Patients with Observations on "PostSurgical” Immunoprophylaxis and Local Immunotherapy RODNEY A. GOMEZ, M.D., FACS, FPCS, FICS, FPCC * INTRODUCTION UNTIL RECENTLY, concepts in the treatment of cancer in general have been centered on three major modalities, namely: Surgery, Irradiation, and Che motherapy. Mathe’1, however, has succintly emphasized that even the most witty combination of these time-tested approaches takes care only of approxi mately one-third of the total cancer cell population in the average tumor-stricken victim. There remains, therefore, even after a thorough treatment, the bigger, deceptive, and invisible enemy which must be handled and combatted continu ously by the immune defenses of the host down to the ‘“last cell” in a guer rilla type of “cell-to-cell” contact through the relentless cell-mediated vi gilance of a battered immunologic sys tem which manytimes has been rendered ♦Chief of Surgery, Doctors Hospital, Bacolod City. incompetent in the latter stages of the warfare. Because of repeated failures of these orthodox methods (mentioned above) to achieve acceptable cures and survivals, the pendulum of therapeutic posture in cancer has swung from one modality to the other, oftentimes with mixed feeling of confusion even among the sturdiest proponents of a particular modality. It should be emphasized that surgery, irra diation, and chemotherapy are by them selves immunosuppressive procedures and that although their initial effects are encouraging, the patient is frequently overwhelmed and overcome in the latter stages by unopposed and revitalized can cer cells. He, in effect * has become a vulnerable victim, for his defenses have been rendered immunologically impotent by the standard procedures. During recent years, with some knowl edge in human immunology, in a “last ditch” effort to salvage patient survival 293 294 Gomez in cancer, Immunotherapy has become a beaconing light to some workers. In its incipient stage, the fascination is great, but there is apparently little to offer to the despondent cancer populace. There is a dearth of local experience in this field as it is abroad. However, it is con ceded that the specialty of Cancer Im munology is gradually but steadily taking shape inspite of tremendous difficulties. It was only during the last decade that we were afforded a clearer understand ing of the Human Immune System relat ive to its behavior in the cancer victim as expounded by Gordon and Ford2 and by Dmodchowski and Bowen8. This has brought us an articulate definition of what actually takes place in the host with respect to tumor-specific antigen recognition, processing, specific cellmediated activation, and cytoeffector im mune response to tumors recognized as non-self that we are provided a means not only for a more effective immuno logic approach to the management of cancer but also to elucidate the basic question of how malignant cells manage to escape immunologic destruction. Through a gradual accumulation of the most recent information on the subject as exemplified by the work of Hellstrom4, we understand now the sluggish and often suppressed immune system of the ad vanced cancer patient in contrast to the heightened Immunity among non-cancer and cancer-reeovering patients. It is with this utter helplessness, impotence, and non-responsiveness of the immune defenses of the cancer victim, and the challenge brought about by the possibi lity of superactivation and utilization of the immune potentials of the non-caneer and cancer-recovering patients through specific and non-specific immunoactiva Sept.-Oct., 1976 J.P. M. A. tion that this work was conceived. The allergory is akin to a drowning man who cannot swim. Utterly helpless and doomed to die, he needs a rescuer in the person of a competent swimmer. In our country, the report of Villasor5 on the immunopotential effects of BCG in advanced cander in 1961 and 1965 was initially encouraging, but lasting results were not as dramatic. This however, was a giant step in cancer immunotherapy in our country. The trophoblastic hypothesis of Navarro6 in the midsixties was challenging and probed into the pos sibility of further investigation into the “riddle of cancer” in an effort to develop new concepts, diagnostic procedures, as well as methods of treatment. In retro spect, the discovery of Alpha Fetopro tein (AFP) by Abelev in 19637 and of Carcinoembryonic Antigen (CEA) by Gold and Freedman in 19658 as immunodiagnostic procedures may have mir rored themselves from the human chorio nic gonadotropin (HCG) test of Navar ro. Gomez® in 1967 reported on the “im munosuppressive nature of cancer, “the significance of lymphocytic infiltration at the tumor-host interface, and the possibility of “cancer rejection” in man. Subsequently, in the same year, immu nopotentiation techniques were initially employed by the same author1®. Lately, Pineda11 ingeniously elaborated on the employment of hemocellular transplant from a healthy syngeneic donor, alone ore combined with BCG administered to advanced cancer patients and reported some beneficial effects in at least two patients but with inconstant and unpre dictable results in others. It is the purpose of this treatise to present a non-heretofore described clinic al study on Transfer and Direct TumorSpecific Immunologic procedures in adVolume 52 Nos. 9-10 vanced human cancer with special at tention to effects on tumor regression, survival time, and mortality, as well as observations on immunoprophylaxis. The author is not aware of any similar stu dy undertaken in our country at this time of writing. MATERIAL AND METHOD Twenty-four patients with various types of malignant and potentially ma lignant tumors, most of them in the mod erately or far-advanced state form the material of this report. There were 7 males and 17 females with ages ranging from 3 to 63 years. Complete history, physical examina tion, pertinent X-rays, and blood counts, particularly the peripheral differential counts including atypical cells when present were routinely performed. Separ ate studies of leucocytic profiles on 53 cancer patients were also undertaken to determine the role of lymphocytes and other cytopathic effectors of cell-medi ated immunity. The patients were clinically grouped into three, namely: Group 1 —Patients whose tumors were adequately removed with no recurrence or spread at the start of the treatment, Group 2 — Pa tients whose tumors were adequately re moved previously but had recurrence or spread at the start of treatment, Group 3 — Patients whose tumors were not ade quately removed and who had recurrence or spread at the start of the treatment. Survival time was always calculated from the first visit or during the start of the immune treatment in all instances. Six patients were operated on between 1-2 years prior to immune treatment but survival times in these patients were counted not from the time of operation but from the immunotherapy. Cancer 295 IMMUNOLOGIC TECHNIQUES Therapeutic manuevers depending upon the presenting need were as fol lows: 1. Administration BCG alone given directly to the cancer patient par ticularly after adequate tumor re moval. In this sense, the thera py may be termed a 4‘Post-Sur gical” immunoprophylaxis. The BCG, given mainly as a recall an tigen and non-specific immunopo tentiator was given intracutaneously at the time of diagnosis at a dose of 0.5 to 1.5 cc similar to the technique of Villasor5 once or twice depending upon the ini tial Delayed Hypersensitivity Re action (DHR). When the first in jection produced a violent or sa tisfactory reaction (3 to 5 cm of initial redness), no second dose was given. When the DHR was poor or timid, a second dose was given 10-20 days after the first. The scarification techniques as ad vocated by Ma the * 1 was not used in this series, although this au thor is contemplating its use on future patients. 2. Tumor — Specific Antigen (TSA) administered directly to the pa tient. This was either given alone or in combination with BCG. This maneuver was also given as a “post-surgical” immunoprophy laxis. The TSA was either allo geneic, syngeneic, or autologous in origin. No typing compatibility was required for allogeneic (non related) TSA as long as the can cer cell type was similar. Tumor-specific Antigens which are actually protein complexes were usually 296 Gomez given subcutaneously either fresh or treated with mitomycin as recommended by Mathe’1. In this series we prefer the former and sometimes use a little ether to reinforce antigen identification. Mi tomycin inactivation was used only in 2 patients (cases 12 and 24). The TSAs were obtained by simple venipuncture in the following manner: (a) As solubilized antigen (detached from the cell) taken from the se rum of the same or another can cer patient (same blood type and tumor) as defined by Pilch and Golub12 and demonstrated clinical ly by Griffiths18. (b) As cell-bound antigen either from the same or another patient with the same cancer cell type from co elomic cavity fluids which were positive histologically for cancer, or from resected tumors or in volved nodes. The antigens from resected tis sues were minced in a sterile man ner in the operating room, and ground before subcutaneous im plantation through an incision se parate from the main operative wound. Those obtained from body fluids and sera were injected si milarly mixed with bacterial prod ucts or enzymes such as polyva lent bacterial vaccines, varidase, or BCG. Part of the resected tu mors was submitted for biopsy and another part was stored in the freezer for future antigenic uti lization. 3. Transfer Immune Factors in form of serum and white blood cells or whole blood administered to the cancer patient subcutaneous ly from a sensitized human donor preferrably but not necessarily Sept.-Oct., 1976. J. P. M. A. syngeneic (related) and of the same blood type as the patient. Sensitization consisted of the do nor having received either TSA as described above, or TSA-BCG combination, or BCG alone when TSA was not available. Transfer Immune Factors were given perio dically, at first 2 times a week for 2-3 weeks, then weekly for 1 month then once every 15 to 30 days, there-after when signs of clinical remission appeared. This was sus tained for a total average of 15 to18 transfers. In this set-up, Transfer Immun ity consisted of the following pos sible constituents, namely: (a) Transfer Factor (TF) as ori ginally demonstrated by Law rence in 195514. (b) Immune RNA is also a pos sibility as demonstrated by Mannick and Egdahl15 and confirmed by Sabadini and Sehon16. This factor, however, is mainly obtained from ani mals (rodents, sheeps, mon keys) rather than humans and is easily inactivated by tissueribonuclease. (c) Serum Factors — (1) Unblocking Serum Factor (USF) — described by Hellstrom, et al1*1 which abrogates the “blocking” of cell-mediated tumor immunity among cancer patients also earlier re ported by the same work ers4. (2) Antibody — Dependent Cellular Cytotoxic factor (ADDC) also called the •'arming” antibody, lym— Voiume 52 Nos. 9-li phocytedependent antibo dy, and “Synergistic” cy totoxicity as recently in vestigated by MacLennan19 and Perlma».in19 4. Local Immunotherapy in cases of cutaneous and subcutaneous can cers either as a local recurrence or metastatic spread to he subcu taneous tissues. In this series an ointment consisting of a combina tion of fibrinolysin and desoxyri bonuclease was applied locally on the cutaneous and subcutaneous tumors daily as abvocated by Kelin20 In cases of metastasis, or when adequate solid tumor removal was impossible because of extensive growth or spread, inductive che motherapy usually with cyclo phosphamide with or without ste roids was initially utilized to red uce tumor burden to at least 105 cells (Mathe’1), or to shrink the lesions to not greater than 1 cm. per cluster even when multiple as advocated by Southam21 to render these residual cells vulnerable to eventual immunologic maneuvers. When initial chemotherapeutic induction has been achieved, or when peripheral lymphocytic po pulation has significantly been red uced to levels below 5,000, the drug was promptly withdrawn and transfer or direct immunity was administered and periodically given until host resistance has been overhelmingly potentiated. As soon as immunotherapy was started, chemotherapy was abso lutely omitted so as not to offset positive immune responses. Cancer 297 Radiotherapy was utilized only in three instances: one for ovarian suppression in a breast cancer, one for recurrent epidernoid skin cancer, and the other, for a neck mass in reticulum cell sarcoma. Chemotherapy and radiotherapy, there fore. were only adjunctive and inductive modalities and were not necessary in the treatment. High dosages of amino-acids and ino sine were given during the whole period of the treatment to potentiate immune cell regeneration and immunoglobulin synthesis as part of a multimodality con cept of treatment ip cancer. For Transfer Immunity, only healthy donors were selected having the same blood type and preferrably but not ne cessarily related (syngeneic) with the patient. The donors usually received TSA with BCG combined, or BCG alone. Full knowledge of the procedure was required and consents were signed by both donor and patient. The cases in this series re flected only those whose families or friends fully consented to the procedure since great difficulty was encountered in the process. A separate group of 33 patients with various types of advanced cancer who had either surgery or chemotherapy but without immunotherapy as described herein was used as control. RESULTS Of the 24 patients, 21 were operated on but only 14 had adequate removal of their tumors, one of whom was a huge recurrent breast tumor which was treat ed like a primary lesion. Eight of these patients had no demonstrable spread or recurrence at the time of immunotherapy while six showed either recurrence or systemic spread. Five patients had 298 Gomez only exploration and biopsy, while two had primary surgery leaving distant me tastases unaltered. Three patients were diagnosed mainly by unequivocal radiolo gic signs (see table 1). The diagnoses of the different tumors are listed in table 2. These were ob tained prior to immunologic treatment. Nine patients had ductal infiltrating car cinomas of the breast, two had chorio carcinoma, and two had reticulum-cell sarcoma. The remaining eleven had one diagnosis each, namely: primary neuro genic cancer of the right lung (neurilem moma), adamantinoma, bronchiolar car-1 cinoma, lung carcinoma (radiologic), tongue carcinoma (epidermoid), medias tinal cancer (radiologic), adenocarcino ma of the pancreas, ovarian carcinoma, esophageal carcinoma (radiologic), giant cell tumor of the humerus with fracture, and epidermoid skin carcinoma, interor bital area. For detailed information of the clinical materials see Plate 1. TUMOR EFFECTS Specific cytopathic effects on tumor of patients whose malignancies were ade quately removed are seen on table 3 and demonstrated the following: (1) Dramatic dissolution of pulmonary, subcutaneous, cutaneous, nodal metastasis or recurrences and ef fusions with stabilization of bone lesions in 3 patients: 2 with breast carcinnoma, 1 with choriocarcino ma (see figures 1, 2, and 3). (2) Intermittent or partial dissolution and growth slowing of recurrent cutaneous and pectoral incisional lesions in 1 patient with recurrent breast cancer one year after ra dical mastectomy, and a recurrent ovarian carcinoma removed 1 1/2 years previously. Sept.-Oct., 1976 J. P. M. A. (3) Absence of recurrence in seven patients with adequate removal of: breast cancer in four, adaman tinoma in one, giant cell tumor in one, and tongue cancer in one. One of the breast cancers in this group was huge local recurrence 24 months after a pervious radical procedure. There was no recur rence 9 months after a second ope ration with subsequent immuno therapy. (4) Marked slowing of bronchiolar cancer adequately removed 24 months previously, and an epider moid skin cancer removed one year previously. Tumor effects on patients whose malignancies were either inadequately removed or not removed at all were noted as follows: (1) Moderate to marked slowing of: a massive neurogenic pulmonary growth, an esophageal cancer with temporary remission and restored ability to swallow, and two breast cancers, one of whom is still alive after 72 months. (2) Progression of tumor growth was ob served in: one lung cancer with me diastinal extension, one pancreatic cancer, one choriocarcinoma, two reticulum-cell sarcomas, and one mediastinal cancer. SURVIVAL TIME Survival times calculated from the first visit or at the start of immunothe rapy are seen in table 4. Group 1 con sisting of 8 patients had a survival time range of 9-96 months with a mean of 35.87 months. As of this moment seven of eight patients (87.5%) as still alive. Volume 52 Nos. 9-10 Group 2 consisted of 6 patients with a survival time range of 6-60 months and a mean of 27.16 months. Five of six patients are still alive (83.33%). Group 3 had only two patients: One survived 30 months, the other only two months, a mean survival time of 16 months. Both patients have died. Group 4 consisted of 8 patients with a survival time range of 1 to 72 months with a mean of 12.25 months. All have died except one (12.5%). Of the total 24 patients, 13 are alive ( * 54.1%) at the time of writing. The overall mean sur vival time was 24.16 months. The Control Group consisting of 33 pa tients with their respective organ can cer listed in table 5 had an age range of 4 to 78 years. 17 were males and 16 were females. The mean survival time were 2.7 months (range 1-18 months). One female patient with a sluggishly growing ductal breast cancer survived 18 months. All patients died at the end of the follow-up. RESULTS OF IMMUNOLOGIC PROCEDURE — The result of the immunologic proced ures employed are seen in table 6. BCG was used alone on cases 2, 3, and 4 of Group 1. Only one had eventual recur rence and died (66.6%). TSA alone was used on cases 1,6,7,8,12,13,15 and 24. Six of eight patients (75%) are still alive, four from Group 1, one from Group 2, and one from Group 4. Transfer Immunity utilizing only BCG which alone was available at each parti cular instance was used on cases 9,11,16, * 17,18,19,21 and 23. Only 2 of 8 patients (25%) are alive, all from Group 2. Transfer Immunity utilizing BCG and Cancer 299 TSA to sensitize the donor plus direct employment of TSA and BCG on the pa tient was used on cases 5,10,14, 20, and 22. Three of the five patients (60%) are alive, one from Group 1, and 2 from Group 2. POST-SURGICAL “IMMUNOPRO PHYLAXIS” This was done on 8 patients in Group 1, on one patient in Group 2, on one pa tient in Group 3, and on three patients in Group 4. Only 7 patients (7 of 8 patients or 87.5%) all in Group 1, are alive, giving an overall survival rate of 53.84% for all groups. TSA was used in 6 patients, TF was used in 4, and BCG in 3. The results are seen in table 7. Interestingly, two cases (1 and 7) with low malignancy (adamantinoma and giant cell tumor) had no recurrence 30 and 47 months after therapy, respective ly. Lymphocytic Profiles Of the 53 patients separately studied for peripheral lymphocyte profiles, 36 were terminal cases while 17 were in the process of clinical remission. Of the ter minal subjects, 13 had lymphos below 10%, 8 with lymphos between 10-15%, 8 had between 16-20%, 5 had 21-30%, while only 2 had over 30%. Of the remitting cases, no patient had below 10% count, 10-15% count, or 16-20% count. Eleven had counts between 21-30% while 6 pa tients had over 30%. The results can be viewed in table 8. Atypical lymphos as an expression of blastogenic responses were observed on two patients. In one of these, a significant eosinophilia was observed (35%). The same patient had a dramatic dissolution of metastatic le sions. Examples of unfavorable and fa vorable lymphocyte responses are seen in table 9. 300 Gomez This author was able to observe sig nificant lymphocytic increases with ino sine and essential amino-acids in con junction with immunotherapy. In one remitting patient (case 14) for instance, an initial count of 25% on 8-2-75 in creased to 37% on 8-16-75 without signi ficant change in the total WBC. A si milar observation was seen in cases 9, 10, 17, and 23 who were maintained on these adjuvants throughout the length of their treatment. Local Immunotherapy Local Immunotherapy with combined fibrinolysin and desoxyribonuclease was uwsed in the cutaneous and subcutaneous lesion on cases 9, 10, and 14. Case 9 had intermittent flattening while cases 10 and * 14 had dramatic disappearance reflect ing also probably not only local but also systemic immune responses resulting from TSA and TF. DISCUSSION The study of cancer has often fascin ated surgeons, pathologists, radiologists, and biologists alike. Surgeons often ca pitalize on the excisional approach and have been able to prolong survival times in cases of purely localized malignancy. When the extent of the lesion is precari ous, the long term results are poor and it becomes the duty of the chemothera pist and radiotherapist to render adju vant aid at a stage when host resistance has obviously waned. Frequently, the latter two modalities enhance rather than check tumor growth particularly when doses are inadequate because of their in herent capacity to further immunosup press biologic defenses in the same manher that surgery does to the patient, the difference being that surgery produces a rebound immunologic response probably because of tumor burden reduction as Sept.-Oct., 1976 J. P. M. A. hypothesized by Simmons * 2. It is now known that the above men tioned modalities can only cure about one-third of the cancer patients when treating perceptible disease!. This leaves a considerable amount of imperceptible tumor cells which comprises the residual, insiduous, and upredictable enemy. This is that particular state of affairs that brings recurrence and eventual demise of the immunobiologically helpless can cer patient. Many-times, one would only hope that the left-over cell burden would not exceed the capacity that can be handled by the existing immune defense in a particular patient. It is in this concept that a multimodality approach to cancer treatment has been advocated by Haskel23. The role of immunotherapy in the treatment of cancer although slow in its development, has lately gained momen tum with a better understanding of “bio logic immunodynamics”. The finding by this author in 19671° of the immunosup pressive behavior of cancer as revealed by absence or scanty lymphocytic infil tration at the tumor-host interface has given insight into the need of some ma neuver that would bring about a po tentiation of the host resistance. Expe rience has shown that most patients with advanced cancer and, therefore, with considerable tumor burden have an al most absolute refractory immunosup pression not responsive to ordinary non specific immunostimulants such as BCG or other bacterial vaccines as advocated by Villasor5, or to non-sensitized hemoCellular transplant as reported by Pine da11, hence, the unpredictability of these immunologic procedures. In advanced cancer patients with sev ere immunosuppression, intracutaneous Volume 52 Nos. 9-10 BCG did not produce a reaction (7 pa tients) even after repeated inoculations, showing obvious anergic status. In some patients with minimal immunosuppress ion, however, hemocellular transplant it self could be beneficial probably because of Hellstrom’s USF. This is one of the components (serum factors) this author relied on during transfer immunization. Physiology of the Immune System There are unequivocal evidences to show that immunity of tumors are exer cised by the Cellular or Lymphocytoid Division rather than by the Plasmacytoid Division of the Immune System as amply described by Gordon and Ford24. The schema of the Physiology of the Immune System is seen in figure 4. The sensitized T-lymphocyte which has mat ured through the thymus and, therefore, thymus oriented is the obvious cytopathic effector, However, if the T-lymphocyte is not tumor-specifically sensitized, then the USF is non-effectual since the unop posed cytopathic effector mechanism has no specific direction or target cell. For this reason, non-specific hemotransplant is of no physiologic value. The most Ideal and rational approach is tumor specific sensitization and/or transfer im munity from a healthy, syngeneic, speci fically sensitized donor. The Plasmacytoid or Humoral Division which is represented by the B-cell or bursa oriented cell, so called because in the chicken these cells are derived from the hindgut bursa of Fabricius, is in man derived from the lymphoid follicles of the Peyer’s Patches and probably the appendix. These plasmacytes elaborate immunoglobulins or serum antibodies which are mainly responsible for immune responses in bacterial infections, foreign body and allergic reactions. They seldom Cancer 301 take part in tumor immunity. More over, by creating antigen-antibody com plexes with tumor receptor sites, they may actually enhance tumor growth pro ducing the so-called “Serum Blocking Factor” SBF) earlier reported by Hellstrom4 (see figure 5). This is the more plausible explanation of cancer patients who inspite of high titres of tumor anti bodies are unable to “reject” their own tumor lending credence to the hypothesis of the immunosuppressive behavior of cancer in its autonomous stage10. Tumor-Specific Antigen One of the various new properties which characterize cancer cells is the ac quisition of protein complexes which have not been present or defined in the cell prior to malignant change. The exis tence of these TSA in both animal and human tumors has been recognized for years3. The malignant cell may carry a variety of antigens, either intracellu lar or at the cell surface. These an tigens may be recognized as “foreign” or “non-self” by the host’s immune system, and an immune response may be mount ed specifically against the antigens and against the tumor cells that bear them. The immune response is usually believed to be cell-mediated (Lymphocytoid Divi sion) and the mechanics is similar to a transplantation rejection process. It is to be emphasized here that the cancer cell is distinct from the antigen itself. It is therefore, with practical importance that we distinguished our approach in securing the TSA into the so called “so lubilized” or cell-free, and the “cell bound” antigens, the former obtained by simple venipuncture, the latter by sur gical excision, aspiration of coelomic fluids, or biopsy. Griffiths13 has shown that cancer cells 302 Gomez abound in the blood in 42 of 70 patients (60%) even among silent, localized colo nic cancers. It is obvious, therefore, that the score could be up to 90% when it comes to cell-bound antigens in cases of full-blown metastatic cancer. This au thor, moreover, predicts an almost 100% availability in the peripheral blood in ca ses of solubilized antigens. In the fu ture, it will be an expedient plan to set up a bank of fresh frozen cancer tissues of various types as a vaccine pool similar to the one described by Mathe’ 1 at the Institute of Cancer and Immunogenetics in France. In this report, the author has introd uced specific immunization by way of immunoprophylaxis, cancer suppression, and transfer immunity with the end in view of a well-directed specific immune response. From the data presented, there was no recurrence of the tumor 30, 21, IS, 9, 42, 47, and 96 months, res pectively, in Group 1, all patients being presently alive (100%). One patient aged 30 (case 6) suffered no recurrence and is alive 42 months after initial surgery and immunization inspite of one pregnan cy during the follow-up period. There was only one patient (case 2) whose growth slowed (24 months) but devel oped metastases and died. There were two patients in group 2 with TSA im munization. One had a dramatic disso lution of pulmonary metastases and is alive today 60 months after initial im munization (see figure 2). The other pa tient had growth slowing of an epider moid carcinoma of the interorbital skin but latter died of cerebral spread 24 months after immunotherapy. One pa tient in Group 3 and one in Group 4 had marked slowing of growth, but eventual ly, of the 8 patients with direct TSA ad ministration in all groups, six (75%) are Sept.-Oct., 1975 J. P. M. A. alive between 24 to 96 months after im munotherapy. Deaths in Groups 2 and 3 merely reflect the factor of tumor bur den which runs pare’ pasu’ with tumorinduced immunosuppression and is often times a decisive element in determining immunologic victory or defeat. It has been conceded by cancer im munologists that tumors with sizes over 1 cm. are difficult to disintegrate immu nologically. The experience in this se ries, however, have shown that metasta sis as big as 1 inch even when in multi ple clusters all over the body dissolved dramatically as early as one to two months time as exemplified by cases 10, 11, 12, and 14 (see figures 1, 2, and 3). Some big solid tumors may pose as im penetrable barriers, although a “second set” type of homograft-like rejection may occur similar to the “Gell’s perivascular islands” of Jones25 which can cause an acute ischemia, necrosis, and dissolution regardless of tumor size. The specificity of tumor antigens to induce corresponding specific reaction is exefnplified by the work of Hellstrom and associates26 who observed inhibition of various tumor cultures by autogenous or allogeiieic leukocytes from patients with the same type of tumor in 88 to 91% as against 3 to 7% of normal cell cultures. Most interestingly, leukocytes from can cer patients caused destruction of allo geneic tumor cells of the same type but not tumors of other histologic types. The recent clinical trial by Marcove, et al27 of autogenous vaccines in the treatment of osteogenic sarcoma merits attention. Southam21, in his experiments in mice observed that tumor-takes of transplant ed methylcholanthrene-induced sarcoma were only 50% less'in immunized than non-immunized animals. Experience in Volume 52 Nos. 9-10 man although not well controlled, showed that reduction of takes was not more than 50% of control values, and to get approximately to that degree, it takes a ratio of 1,000 leucocytes to 1 tumor cell for an effective cell-to-cell contact. The preparation of the tumor-specific antigen itself deserves mention. Accord ing to Southam21, the most effective form of tumor vaccine is the intact tumor cell, either viable, or metabolically alive but treated with chemicals, bacterial prod ucts or irradiation to prevent cell propa gation but retains as well as reinforces its antigenicity as suggested by Rios and Simmons38. This author suspects that in big solid tumors antigenicity is nil if the host-tumor interface remains as a thick barrier leaving no means of “immunolo gic exchange” between the tumor and the host, thereby perpetuating unchecked tumor growth. When the tumor eventual ly finds its way to the blood stream, im munosuppression has gone too far for the host to take care. Thick TSA tis sues when not comminuted adequately and attenuated as described prior to sub cutaneous implantation may produce a “take” which occurred in one patient in earlier experiments. The lesson was learned and subsequently corrected. When severe immunosuppression has prevailed, TSA alone may be too weak to evoke a response. The use of TSA in combination with BCG becomes an al ternative. This is a simpler method de void of moral and donor problems when compared with Transfer Immunity. Re cent reports by Powles28 showed drama tic results among patients with acute myelogenous leukemia using stored viable tumor cells plus BCG. Fefer, quoted by Simmons22 described 12 patients who re ceived subcutaneously their own leuke mic ceils, lethally irradiated in vitro with Cancer 303 10,000 rads plus intravenous infusions of peripheral lymphocytes from a normal identical twin. Complete remissions occured in 87% of cases with six patients having complete remission at 11 to 44 months without chemotherapy. The cultured cell-BCG immunization techni que of Sokal and Aungust29 is merely a variation. Recently, Rosato30, et al used Vibrio cholera neuraminidase as an adjunctive treatment with monthly injections of autochthonous tumor cells to 25 patients with various types of cancer. Six who received the full course of 6 injections are all alive without clinical evidence of progression more than 8 months after the start of treatment. It is clear, therefore, that the TSA may need some sort of immunopotentiation in the more advance ype of cancer with severe im munodepression. The adjunctive treat ment apparently reinforces the TSA by causing a DHR through the following mechanisms, namely: 2) production of a less rigid cell surface structure allowing easier membrane deformation and pha gocytosis of the TSA by macrophages, b) unmasking of antigens allowing greater recognition, and (c) facilitation, and accessibility of antibodies to antige nic receptor sites on the surface of the cancer cell. Employing cytotoxici ty assays in vitro using autologous tar get cells grown in tissue culture, Rosato30 observed cytolysis without tumor en hancement or “blocking” effect in 4 of 5 patients in whom this was measured, In this series, TSA combined with BCG was not used alone but in conjunction with Transfer Immunity by reason of exi gency. Of 5 patients where this was used (case 5, 10, 14, 20, and 22), 3 or 60% are alive. The non-response of pa tients in group 4 (cases 20 and 22) was 304 Gomez due to overwhelming tumor load and im munodepression . Transfer Immunity Lawrence14 in 1955 was the first to report on the rtansfer of delayed hyper sensitivity responses to tuberculin and other antigens in man with dialyzable extracts of human peripheral lymphocy tes. This was termed the “Transfer Fac tor” (TF). In 1960, specific accelerated rejection of skin homografts in man were found to be mediated by this factor by the same authors31. Although its use has been confirmed in non-cancer immune deficiency diseases such as Wiscott-Aldrich syndrome, its more dramatic role in recent years has been focused on malig nancy. It is similar but distinct from Immune RNA of Pilch and Golub12, the difference being on the fact that the for mer is obtainable from the lymphocytes of man while the latter mostly from that of animals and is, moreover, inactivated by tissue ribonuclease while the TF is not. Ribonuclease, however, can be in activated in turn by low molecular weight dextran. Southam21 refers to Lawren’s TF as “Instructional Immunotherapy” for al though it does not contain the antigen to which immunity is conferred, nor is an tigenic of itself, it somehow transmits Information which “instructs” the reci pient’s immune system to respond to the same antigen which sensitized the donor. The appeal then for such non-antigenic material for immunotherapy is obvious based on the assumption that healthy do nors who have built up immune resis tance to a wide variety of cancer cells could offer their leucocytes to the can cer recipient who is unable to defend himself against the malignancy. This was precisely the concept utilized by this Sept.-Oct., 1976 J. P. M. A. author in this treatise. With the ad ministration BCG to the donor, he ac quires a heightened, non-specific immu nity, but with the addition of TSA, he develops, in effect, a specific, hightened immunity when transferred “instructive ly” to the cancer patient and confers not only a recall DHR but also a specific cytotoxic instigator to a remarkable deg ree. When using transfer elements including serum instead of just only leukocytes as originally used by Lawrence14, this au thor also availed of two serum factors aside from the possible availability of Immune RNA. The serum factors, pre viously mentioned are: (1) USF of Hellstrom, and (2) ADCC factor of MacLennan and Perlmann. Two patients, in Group 2 where trans fer BCG was used are both alive (cases 9 and 11) 41 and 12 months, respective ly. The rest of the patients who received transfer BCG all died, one belonging to Group 3 and five from Group 4. One of the above survivors (Case 11) had dramatic dissolution of abdominal spread and ascites. The over-all effectivity for all groups with transfer BCG was a poor 25% reflecting severe refractory immu nosuppression. In comparison, the ef fectivity of 50% for combined Transfer and Direct Immunity utilizing TSA plus BCG for both approaches seems encour aging and should be used more often in advanced cases. It is observed however that transfer BCG was used more often than transfer TSA. The reason is re luctance on the part of the donor in ac cepting the procedure for fear of cancer propagation. However, the argument it self is not valid, first, because the TSA is initially deactivated by pre-treatmenx as previously described, and second, be * cause of the concept of Immunologic Volume 52 Nos. 9-10 Surveillance in healthy individuals as ad vanced by Burnet32. Survival Time and Mortality The mean survival time in this series of 35.8 months in Group 1 and 29.2 months in Group 2 is indeed encouraging. For example, in Group 1 we had a su perextended survival of 96 months in one patient and over 40 months in two, and the rest between 9-30 months with only one death. The mean survival among patients given autologous tumor cells treated with Vibrio cholera neuramini dase after surgery by Takita, et al, as quoted by Simmons22 was only 17.4 months. Although the mean survival time in Group 2 was only 29.2 months, the long est survivals for this group were 60 and 41 months, respectively. The rest had between 12 to 24 months with only one death at the end of the follow-up. Group 3 and 4 did not fair well (16 and 12.2 months mean, respectively), although one patient who is still alive has a 72-month survival time. These results speak co gently for themselves when compared with the 33 control patients without im munotherapy who had a mean survival time of 2.7 months, all of whom have died. Comparison with the BCG group of Villasor5 (see table 10) which had 7 sur vivors out of 43 patients (16.2%) at 24 months, the survival in this series were 10 out 24 patients alive 24 to 96 months (41.6%), while the actual number of living patients is 13 (54.1%) which is highly significant. The results in Group 1 and 2 are inspiring and should invite more attention and study as well as em ployment of bigger and adequately con trolled series. It is, moreover, obvious from this data that tumor burden is a Cancer 305 critical factor if immunotherapy is to succeed. The poor results in Groups 3 and 4 are witness to this fact. Lymphocytic Responses The study of peripheral lymphocytes in this series deserves mention since they are the principal agents of immunity against tumor cells. As early as 1922 MacCarty33 has already mentioned the significance of lymphocytic infiltration around breast cancers as a determinant in host rejection of the tumor and a favorable prognostic sign relative to sur vival. It is unfortunate that this obser vation was discredited for half a century before eventually gaining some support. Evidences have shown that lymphocy tes become significantly reduced in a good number of patients whose progress is dismal. As a matter of fact, the dec rease or increase of the lymphocyte popu lation is of prognostic significance which will presage whether the patient is go ing to succumb to the disease or get well in the not too distant future. In the authors * personal unlisted experience, the forst and most accurate prognosis were on those patients whose lymphocyte counts slumped below 10% pare’ pasu” with very high total WBC counts be yond 15,000. The appearance of atypical cells in two patients (cases 10 and 18) was sug gestive of blastogenic repsonse which according to Pilch and Golub12 is indic ative of prior sensitization of lymphocy tes to tumor antigens. This may, there fore, be interpreted to represent detect ion or recognition of TSA by the host. The appearance of significant eosino philia in one patient (also with atypical lymphos) with dramatic tumor dissolu tion indicated either the presence of a Sept.-Oct., 1976 J. P. M. A. 306 Gomez foreign agent, an allergic reaction, or an antigen-antibody repsonse. By elimina tion, the latter may be the most likely mechanism to explain this occurrence. This antigen-antibody phenomenon has been amply expounded by WetherleyMein34 who claimed that eosinophils are involved in the initiation of antibody syn thesis. It appears that antigen-antibody complexes could be phagocytosed by eosinophiles. Defense against pathogenic effects of immune complexes by eosiphiles is significant in the light of Hellstrom’s SBF * . Other functions of the eosinophiles are fibrinolytic activity and histamine inactivation whose relation ship to cancer is still unknown. <<Post-Snrgical” Immunoprophylaxis Cancer Immunoprophylaxis in the strict sense of the word refers to immu noprocedures performed on the non-cancer patient to prevent a future occur rence of the actual cancer. In this stu dy the term immunophylaxis was used rather loosely and was preceded by the word “post-surgical” to qualify succinct ly what this author had in mind. The word was used only with respect to those patients who had actual removal of the tumor and were given either BCG, TSA, both, or with TF. From the figures in this study, immu noprophylaxis was effective only when the tumor was adequately removed. The figure of 87.5% effectivity (7 of 8 pa tients) clearly justifies the procedure, al though a bigger series would be more convincing. Moreover, immunoprophy laxis may be effective even with tumors of low malignancies as seen in two pa tients. To date, only two other human experiments had been done aside from this present series. One was by Bjorklund35 who inoculated small groups of elderly men with a vaccine containing a mixture of human tumor cell in the hope that the resulting homograft immunity would inhibit the development of future cancers. Up to the present, however, no follow-up reports had been published. The flaw in this experiment, however, is that the prophylaxis was made late in life, although it can be opined that this is the age when tumors occur more fre quently and, therefore, demands preven tion. The other study was a collabora tion between the group from Sloan-Ket tering Institute, and that from Ohio State University Medical School36 with the pri mary objective of studying homograft re jection phenomena and TSA. In that experiment, nearly 300 volunteers in the Ohio Penitentiary received living tissue culture cell homografts of various hu man cancer cell lines. Long-lasting ho mograft immunity directed toward TSAs was demonstrated in these men. The follow-up was between 14 to 20 years, and although it was difficult to trace every body because of frequent change of abode, those who were account ed for ten years or more from the time of inoculation (about one-third of the original number) showed only two known cases of cancer (2%). Although no conclusion was possible, immunoporphylaxis, either post-surgical or the true preventive measure is a fascinating pro cedure which will do doubt find its place in our future conduct with cancer-prone patients. Local Immunotherapy The subject of local immunotherapy for superficial lesions merits attention. Klein, et al20, in his experiences with basal-cell and breast cancer (recurrent) as well as mycosis fungoides using locally applied dinitrochlorbenzene (DNCB), streptokinase-dornase, and PPD showed eradicaVolume 51 Nos. 9-10 tion of skin cancers in 95% in a grousa of 90 patients. The mechanism is brought about by DHR to haptens of re latively small molecular weight produ cing selective antitumor effects against malignant and premalignant epidernal lesions and lead to their eradication. Of three patients where local immunothera py was used m mis series, all responded with either flattening or complete disap pearance of cutaneous and subcutaneous lesion (100%). The Donors The donors selected for transfer im munity were preferrably of the same blood type and related to the patient. This is merely to avoid the usual problem with histocompatibility antigens encount ered with non-syngeneic donors during subsequent transfers. The experience here, however, has shown that non-related isotyped donors did just as well with excellent results even -after over 12 trans fers (cases 10 and 14). A history of hepatitis not only in the prospective do nor but also in the patient is an abso lute contraindication to transfer immu nity. TSA in this case is the logical re course. Adjunctive Therapy The discussion of immunotherapy will not be complete without certain factors which may be responsible for adequate lymphocyte production. Protein is one of the most vital raw material which can accelerate cell production. Preferrably, this should be in essential amino-acid form when assimilated by the patient in order to facilitate prompt synthesis without undergoing too much digestive work when introduced orally. Interes tingly, amino-acids in contrast to the usual natural complex protein, passes through the gut into the portal system Cancer 307 to the liver frflftte without ®iuch ado and there undergo rapid protein synthe sis. It is even more effective when ad ministered intravenously. Hypoproteinemia is a common obser vation among advanced cancer patient probably because ot nausea, inanition, poor absorption, and deficient protein synthesis. This results in poor body re sistance and immunodepression. Patients given amino-acids, however, regain their serum protein values and, consequently also, their lymphocyte and antibody ca pacities, and frequently experience some kind of remission. The role of Inosine in reversing lym phopenia either after chemotherapy, ra diotherapy, or because of cancer immuno suppression itself has been firmly estab lished by Kondo and Aoyama87 in 1965. Lymphocyte regeneration is probably by way of the Inosine-RibosephosphateAMP-ADP-ATP pathway facilitating nu cleotide and protein synthesis even un der conditions of hypoxia. In this series at least 20% of the cancer patients were brought to satisfactory lymphocytic le vels either after inductive chemotherapy or during the immediate cost-surgical period. This phenomenon cannot be ex plained solely by the effect of immuno therapy alone. SUMMARY Twenty-four patients with various types of cancer were given transfer and Direct-Specific Immunizations which at times were reinforced with BCG under conditions of exigency. The patients were grouped as follows: Group 1— Tu mors adequately removed, no metastasis or spread, Group 2 — Tumors adequate ly removed previously but with existing spread or metastasis at time of immu notherapy, Group 3 — Tumors not adeCancer 309 Vnlunvt 52 Nm. 9-10 Volume 52 Nos. 9-10 Cancer 311 PHYSIOLOGY OF THE IMMUNE SYSTEM X V ..............AFFERENT ] CENTRAL > LIMBS ------------ EFFERENT J FIGURE 4 quately removed, with local or systemic spread, Group 4 — Tumors not removed, with local or systemic spread. In group 1, all are alive except one (7/8. or 87.5%) between 9 to 96 months (mean 35.8 mo.) with recurrence of tu mor only in one patient. In Group 2 (6 patients), four had dramatic dissolution of the spread and recurrence, two had growth slowing and all are alive except one (5/6 or 83.3%) 6 to 60 months. (mean 27.1 mo.). In Group 3 (2 pa tients), all died with a mean survival time of 16 months. In Group 4 (8 pa tients), only one is alive (12.5%) after 72 months, with a mean survival time of 12.2 months. Control studies in 33 advanced cancer patients without Im munotherapy revealed a mean survival time of 2.7 months, with no living pa tient after that period. Survival time was calculated from the first visit or inSept.-Oct., WTb J. P. M. A. 312 Gomez FIGURE 5 stitution of immunotherapy and not from the previous operation. Compari:on with Villasor’s series was discussed. In cluded in this study was an experience with local immunotherapy for cutaneous lesions. Tumor burden was a critical factor as shown in Groups 3 and 4. The results in Groups 1 and 2 were encouraging and invite more attention, study and employ ment of bigger semes. “Post—Surgical” Immunoprophylaxis W’as discussed relative to its effectivity (7/8 or 87.5%) in Group 1 and an over all survial rate of 53.8% for all groups. The role of lymphocytes as cytopathic * effectors of cell-mediated immunity as well as the prognostic significance of its peripheral population has been empha sized. The presence of atypical cells and significant eosinophilia in some patients and their relationship to antigenic recog nition and tumor antigen-antibody inter action was mentioned. Finally, the rege nerative potential of Amino-acids com bined with Inosine in conjunction with Immunotherapy was revealed by improve ment in lymphocyte levels which cannot to explained solely by immunotherapy alone. Volume 52 Nos. 9-10 Cancer 313 Plate 1. TRANSFER AND DIRECT TUMOR-SPECIFIC IMMUNITY. SPECIFIC TUMOR EFFECTS AND SURVIVAL Group 1 — Case Age Sex Cancer Tumor Effects Survival Time in Months Present Status 1 50 F Jaw NR 30 A 2 51 F Lung MS 24 D 3 50 F Breast NR 21 A 4 53 F Breast NR 18 A *5 54 F Breast NR 9 A 6 38 F Breast NR 42 A 7 3 M Bone NR 47 A 8 63 M Tongue NR 96 A * second operation for local recurrence Group 2 — 9 55 F Breast PD 41 A 10 36 F Breast DD 20 A 11 52 F Ovaries PD 12 A 12 22 F Trochoblast DD 60 A 13 48 F Skin MS 24 D 14 47 F Breast DD 6 A A. With Surgery-.......... ................... •.................... (21) 1. Adequate Tumor Removal ......... 14 Group 3 — 15 16 54 52 F F Breast Prophoblast MS PG 30 2 D D Group 4 — 17 50 F Lungs MS 10 D 18 58 M Lungs PG 2 D 19 7 M RES PG 5 D 20 58 M Pancreas PG 3 D 21 62 M Esoph. PD 3 D 22 61 F RES PG 2 D 23 60 M Mediast. PG 1 D 24 55 F Breast MS 72 A Legend: NR—No recurrence, MS — Marked slowing of growth, PD—Partial dissolution, DD — Dramatic dissolution. PG—Progression of growth, RES — Reticulo-endothelial system D — Dead, A — Alive Plate 1. CLINICAL MATERIAL C I a s s ification No. of Patients a) no spread ................................ 8 b) with spread .............................. 6 2. Inadequate Tumor Removal .............................. 2 3. Exploration or biopsy only .................................. 5 B. Radiologic Diagnosis Only .............................................................. ( 3) Total 24) Sept.-Oct., 1976 J. P. M. k. 314 Gomez Table 2. DIAGNOSES OF MATERIALS Tumor No. of Patients Duct Carcinoma, Breast ........................................................ 9 Choriocarcinoma ........................................................................ 2 Reticulum-Cell Sarcoma .......................................................... 2 Esophageal Carcinoma (radiologic) .................................... 1 Neurogenic Sarcoma, Lung .................................................... 1 Giant Cell Tumor, humerus with fracture.......................... 1 Adamantinoma ............................................................................ 1 Epidermoid Skin Cancer .......................................................... 1 Bronchiolar Carcinoma, Lung ........................................... 1 Lung Carcinoma (radiologic) ................................................ 1 Tongue Epidermoid Cancer .................................................... 1 Mediastinal Cancer (radiologic) ............................... 1 Adenocarcinoma, pancreas ......................................... 1 Ovarian Carcinoma .................................................................... 1 TOTAL 24 Table 3. SPECIFIC TUMOR EFFECTS WITH TRANSFER AND DIRECT TUMOR-SPECIFIC IMMUNITY Classification No. of Patients A. Tumors Adequately Removed .............................................. (14) 1. Dramatic dissolution .............................................. 3 2. Intermittent or partial dissolution .................. 2 3. Absence of recurrence .......................................... 7 4. Marked slowing of growth ........................... 2 B. Tumors Inadequately or Not Removed .................. (10) 1. Moderate to marked growth slowing.................. 4 2. Progression of tumor growth .............................. 6 TOTAL.............. 24 Table 4. SURVIVAL TIME AND EFFECTIVITY RATE Group No. of patients Range-mo. Mean-mo. Survival Ratio % Alive. 1 8 9—96 35.87 7/8 87.50 2 6 6—60 27.16 5/6 83.33 3 2 2—30 16.0 0/2 0.00 4 8 1—72 12.25 1/8 12.50 AU Groups 24 1—96 24.16 13/24 54.10 Control 33 1—18 2.7 0/33 0.00 Volurrie 52 Nos. 9-10 Cancer 315 Table 5. ORGAN CANCERS IN 33 CONTROL PATIENTS — Organ Site No. of Patients Lungs 9 Breast 7 Liver 4 Skin and Subcutaneous Tissue 3 Colon, Rectum 2 Cervix 1 Pancreas 1 Esophagus 1 Intestines 1 Bone Marrow 1 Muscle 1 Bone 1 Pleura 1 TOTAL................ ................ 33 Agents Used Table G. Case IMMUNOLOGIC PROCEDURES Group Tumor Effects Result % Alive A) BCG Alone 2 1 MS Dead 3 1 NR Alive 2/3 (66.6%) 4 1 NR Alive B) TSA Alone 1 1 NR Alive 6 1 NR Alive 7 1 NR Alive 8 1 NR Alive 6/8 (75%) 12 2 DD Alive 13 2 MS Dead 15 3 MS Dead 24 4 MS Alive C) TFusing BCG 9 2 MS Alive 11 2 DD Alive 16 3 PG Dead 17 4 MS Dead 2/8 (25%) 18 4 PG Dead 19 4 PG Dead 21 4 MS Dead 23 4 PG Dead D) TF Using TSA +BCG 5 1 NR Alive 10 2 DD Alive 3/5 (60%) 14 2 DD Alive 20 4 PG Dead 22 4 PG Dead Legend: DD-Dramatic dissolution, NR-No recurrence, MS-Marked Slowing, PG—- Progression of Growth. 316 Gomez Sept.-Oct., 1976 J.P. M. A. Table 7. IMMUNOPROPHYLAXIS Group No. of Patients Alive % Dead 1 8 7(87.5%;) 1 2 1 0 (0%) 1 3 1 0 (0%) 1 4 3 (biopsy only) 0 (0%) 3 Total 13 7(53.84%) 6 Table 8. LYMPHOC/TE PROFILES IN 53 CANCER PATIENTS A. Terminal Patients (36 Patients) Lymphocyte Count: Below 10% 13 10—15% 8 16—20% 8 21—30% 5 over 30% 2 B. Remitting Patients (17 Patients) Lymphocyte Count: Below 10% 0 10-15% 0 16—20% 0 21—30% 11 over 30% 6 Table 9. UNFAVORABLE AND FAVORABLE RESPONSES RELATIVE TO LYMPHOCYTIC PROFILES AMONG CANCER PATIENTS (a) Unfavorable — (.untreated) (1) Patient E.T., 33 yrs., F — Breast Cancer Initial Counth — WBC — 17,000 lymphos—14 Eost-2 Subseq. Count — WBC — 19,000 lymphos— 7 Ebs-0 Result: died (2) Patient R.T.. 40 yrs., M — Lung Cancer Feb. 3, 1967 — WBC — 13,500 lymphos — 19 Eos-1 Feb. 14, 1967 — WBC — 25,000 lymphos — 9 Eos-1 Result: died (b) Favorable — (With Immunotherapy) Patient L.S.. 36 yrs, F (Case 10) — Breast Cancer Jan. 19, 1974 — WBC — 17,000 lymphos — 3 Eos-11 March 29, 1974— WBC — 17,000 lymphos — 25 Eos-35 atypical Result: (lymphos seen) Dramatic Tumor Dissolution, Alive Table 10. COMPARISON BETWEEN SPECIFIC AND NON-SPECIFIC IMMUNOTHERAPY Workers No. of Patients Survival Time Survivors % Villasor 43 at 24 months 7 16.2 This Author 24 24—96 months 10 41.6 (do) (do) 6—96 months 13 54.1 (present survivors) Volume 52 Nos. 9-10 BIBLIOGRAPHY 1) Mathe , G.: Current status of immunotherapy of human cancers: leukemias, lymphomas, solid tu mors Med. Prog. 2,5:17-24, May 1975. 2) Gordon, B.L., and Ford, D.K:: Essentials of Im munology, p. 1-19, F.A. 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