Review
INTRODUCTION TO TUMOR IMMUNOTHERAPY
FREDERICK HELM, M.D. , F.A.C. P. ANO JUTA HELM, M .D .
From the D epa rtm ent of Dermatology State University of New York Schoo / 0 { Medicine, Buffalo, New York
. The goal of eaneer immunotherapy is to alter Immune responses of the host to the tumor, enabling th e host to eliminate neoplast ie cells. Animai experiments and trials of imrnunotherapy in humans show that in prineiPie this is feasible. Unfortunately, tumor imrnunotherapy is stili in the preliminary stage, and mueh work remains to be done before it can attain the status of routine treatment. There are different approaches to imrnunotherapy (Table 1). In speeifie immun?therapy, the immune response of an indiVIduai is stimulated against his tumor. In nonspeci fi e immunotherapy, the antitumor effect re su lts from a nonspeeific enhanee~ent of immunoresponsiveness. In active lmrnunotherapy, antigens from the tumors (vaccines of whole tumor eells or subcellular components) are used to stimulate antibody Production. In passive immunotherapy, adrninistration of antitumor antibodies or tran sfer of sensi tized lymphocytes or their Produets, lymphokines, is utilized . A prerequisite for sueeessful immunotherapy is the immunoeompeteney of the patient. Cl in-
ieal assessment of immunoeompetenee ean
be accomplished with a series of standard skin tests outlined in Tabl e 2. lmpaired immunoeompetenee in pati ents with progressive malignant _di s~ase. is a bad prognostie sign. Results of m v1tro Immunologie tests sueh as lymp~oc_yt~. stimulation , maerophage migratlon _mhtbltlon, humoral antibody titration and 1mmunoglobulin levels do not seem to show a significant eorrelation with progression of the malignant di sease. Present evidenee indiea tes th at the immu~ o log ie defense of the host against his ~a!Jgna~ey ean be strengthened by inereastng the Immunologie responsiveness of-the host, inereasing the immunogenieity of the tumor eells, eliminating factors inhibiting the confrontation between lymphocytes and tumor ce lls, and by decreasing the tumor mass by surgery or ehemotherapy .
Specific Adoptive lmmunotherapy At Roswell Park Memoria! lnstitut e, Nadler
Presented at the XV lnternati onal Congress of Derrn atology, M exico City, Mexico, October 19, 1977. Address for reprints: Frederick Helm, M.D., Departrnent of Dermatology, Roswell Park Memoria! lnstitute, 666 Elm Street, Buffalo, NY 14203. 0011-9059/79/ 0400/0205 / $00.80
~nd Moore 1 tried to utilize specifie adopt ive
1mmunotherapy by cross immunizing pairs of pati ents with osteogenie sa reo ma s and
© lnternational Society of Tropical 205
D erm atology, lnc.
206
INTERNATIONAL JOURNAL OF DERMATOLOGY
Table 1.
Active
Vol. 18
Different Types of lmmunolherapy Nonspecific (lmmunopotentiators)
Specific
l
Aprii 1979
With sterilized tumor cells or tumor extracts
Contaci allergens: Trenimon, DNCB
Tumor cells treated with neuraminidase
Microorganisms and their products : BCG, Corynebacterium parvum, Vaccinia Chemical adjuvant s: Levamisole
Il
111
Passive
Antitumor sera obtained from animals immunized with fragments of patients tu mor patients whose tumor had undergone spontaneous regression and whose serum contains antibodies to the neoplasm
Transfer of immunologie active products from an immune donor
Adoptive
Tran sfer of allogenic or xenogenic immune lymphocytes
PHA stimul ated lymphocytes
Transfer factor lmmuno-RNA
melanomas. They cross transplanted their tumors and subsequently exchanged their sensitized peripheral blood lymphocytes. Unfortunately, immunization of patient A with tumor from patient B induced a response to transplantation antigens (HLA). Thus, the subsequent administration of lymphoid cells from patient A to the sensitized patient B led to a rapid destruction of the transfused cells and rarely showed the desired beneficiai effect. There is no evidence that the patients reacted to tumor antigens by forming specific antibodies to the neoplasm. The design of these experiments has been criticized and they have been abandoned. Some of the disadvantages of specific, passive immunotherpy with allogenic lymphocytes can be avoided by using immunologically active celi-free extracts of lymphoid celi products such as the transfer factor, 2• 3 and immune RNA. 4 • 5 lnjections of transfer factor, a low molecular weight extract of leukocytes, can be used to transfer delayed hypersensitivity. This method of treatment is successfully used in chronic mucocutaneous candidiasis and leprosy. The major problem
with the use of the transfer factor and immune-RNA for immunotherapy is lack of easy availability. Norma! subjects have been used as donors, because some may have had a tumor rejected and thus have an immunity to the tumor. Thymus extracts have also been used for immunotherapy. 5 Nonspecific Active lmmunotherapy
A form of nonspecific active immunotherapy for skin tumors has been introduced by E. Klein. 6 - 9 Delayed hypersensitivity reactions at tumor sites following active nonspecific stimulation are used. 6 - 9 In 1964, we reported that some tumors of the skin seem to be exquisitely sensitive to delayed hypersensitivity reactions, much more than the uninvolved skin. This was observed in a patient with multiple superficial basai celi carcinomas treated with tri-ethylene-imino-benzoquinon . 10 As soon as he became sensitized and developed a delayed hypersensitivity reaction, regression of his tumors at the site of the reaction was noted . After these observations, we used other contact allergens in a trial of immunotherapy of tumors involving the sk in. lmmu ~ nocompetency of the patient was established
No. 3
TUMOR IMMUNOTHERAPY
Table 2.
Helm and Helm
Assessment of T Ce li Function
PPD
Purified protein derivative of Mycobacterium tuberculosis (tuberculin).
V arida se®
Antigenic preparation of certain strains of streptococci. Mumps virus extract: this is an indicator of immunologie memory for childhood immunizations or infections. Candida albicans extract (positive in approximately 40% of immunocompetent patients).
Mumps vaccine Candida antigen Trichophyton
Extract of common dermatophytes.
Blastomycin
Blastomyces dermatitidis extract. The organism is found throughout North America . However, because less than l% of the population are positive reactors, blastomycin is a good contro! for negative reaction .
Histoplasmin
Histoplasma caps u/atum antigen skin tests are frequently positive in persons from the southeast regions of the United States. Coccidiodes immitis antigen skin tests are commonly positive in persons from the southwest regions of the United States. Dinitrochlorobenzene (DNCB), used to determine ability to respond to new antigens.
Coccidiodin
DNCB Trenimon
207
2, 3, 5 triethylene-imino-1 ,4 benzoquinone. This compound was used for the same purpose as DNCB. To Assess 8 Celi Fun ction
Testing is done with: Schick antigen
Corynebacterium diphtheriae toxin . The toxin produces necrosis in nonimmune or severely compromised patients. (more than 95% of the population neutralize the toxin).
and then delay hypersensitivity reactions were produced at the tumor. sites. Antitumor effects of the celi mediated hypersensitivity reactions were demonstrated clinically and by seria! biopsies. Tri-ethylene-imino-benzoquinon, dinitrochlorobenzene (DNCB) and nitrogen mustard were employed not only for treatment of severa! type of epidermal cancers and adenocarcinomas of the breast and melanomas but also for malignant lymphomas, esp~cially mycosis fungoides and histiocytic lymphoma. The immunologie reactions produced were independent of the tumor, which was iust an innocent bystander of an immunologie reaction. lt is therefore questionable if such an àpproach merits the classification of immunotherapy. The tumor regression may just have been the result of inflammation at the tumor site, rather than any specific immunologie process directed against tumor antigens. Nevertheless, it must be said that use of primary irritants, for instance, croton o il and burns produced with an ultraviolet lamp,
did not show the striking results seen with the use of tri-ethylene-imino-benzoquinon. The microorganism most widely used in tumor immun'otherapy has been Bacillus Calmette Guerin (BCG), which was obtained through progressive attenuation of a virulent strain of Mycobacterium bovis. 11 So far, the greatest experience has been gained in its use in malignant melanomas and lymphomas. BCG or PPD have been used in the treatment of a variety of cutaneous tumors, occasionally causing tumor regression. Table 3 outTable 3.
BCG Dose Schedule
Oral BCG was given 40 mg per week, 4 times 40 mg per month, 5 times 40 mg every 2 months, 6 times 40 mg every 6 months, 2 times BCG intradermally was given 0.1 mg per week, 4 times 0.15 mg per month, 5 times 0.2 mg every 2 months, 6 times 0.25 mg every 6 months, 2 times
208
Aprii 1979
INTERNATIONAL JOURNAL OF DERMATOLOGY
-- -·----·----•--.--
100"..
---------·
~
------~-6
80 ",, fr ee
40" ..
20" ..
6
12
18
24
30
Vol. 18
Fig. l . Di sease-free interval by sex. Broken fine indicates female pati ents (21); solid fine indicates mal e patients (46). Difference statisti ca lly significantly (p > 0.05).
36 months
d 1sease fr ee 1nt e rval
lines the BCG dosis schedule given to our malignant melanoma patients. Side effects were seen in 40% of our patients receiving BCG by injection or scarification. Fortunately, they were usually mild and included local complications as pruritus, induration, ulceration , BCG lupus, and regional lymph node enlargement. Systemic complications including fever, malaise, chills, vomiting, myalgia, arthralgia, progression of tumor growth, and erythema nodosum were seen occasionally. Vitiligo, uveitis, thrombocytopenia, anaphylactic reaction and death were not observed by us, but have been reported in the l iterature.I2,I3 100" •.
so·· .. d 1St!ilSt.~ lrPt !
''
''
''
Results of BCG lmmunotherapy
The clinica! data of this study were evaluated by the Computer Research Section of Roswell Park Memoria! lnstitute in Buffalo. Life table analysis was done using the Cutler and Ederer !ife table method . Between january of 1972 and December of 1976 immunoprophylaxis (Table 3) was used for Stage l and Il malignant melanoma patients at Rosewell Park Memoria! lnstitute in Buffalo, New York. Sixty-seven persons participated in this study (46 males and 21 females; 21 were under the age of 45, and 46 were over 45 years old). Forty-eight patients had Stage l
·~--------------------,,, >,
p c \tlt ! nt ~
•
'',,, '• 40 '· ·
20 '··
12
l
8
24
d1sease fr ee 1nterva l
30
36 month s
Fig. 2. Disease-free interval by age . Broken fine indicates patients over 45 years old (46); solid fine indicates patients under 45 years o Id (21 ). Difference statistically not significant (p> 0.05).
No. 3
-- -·----·----·----·----.
100"•o
------
---._
80°•o d1 sease
fr ee patlents
Fig. 3. Di sease-free interva l after prophylactic node dissection (Stage l malignant rnelanoma) . Broken line indicates patients without node dissection (26); solid line indicates patients with node dissection (22). Difference statistically not significant (p > 0.05).
209
Helm and Helm
TUMOR IMMUNOTHERAPY
6
12
18
24
30 months
d1sease fr ee 1nt erval
were clinically free of melanoma; after 24 months 70% and after 36 months only 59% . As observed by others, our study confirmed that women with malignant melanoma have a better prognosis than men (Fig. l). Our study comparing patients below and over the age of 45 did not show differences of the disease-free interval depending on age (Fig. 2). Prophylactic node dissection (no clinically ·enlarged palpable lymph nodes) d id not prolong the disease free interval after surgery (Fig. 3). As exp~cted, the disease free interval was much shorter in patients with node involvement (Fig. 4) . The median disease free interval in this group was 5.7 months com-
and 19 patients had Stage Il malignant melanoma. Nineteen received BCG orally and 16 intradermally; 32 melanoma patients were used as controls and remained without immunotherapy. We utilized a strain of living bovine tubercle bacilli (Bacillus Calmette Guerin) provided by the Connaught laboratories in Willowdale, Ontario, Canada. The disease-free interval for patients with Melanoma l (48) and Il (19) after surgery did not differ significantly between the BCG (35 patients) and the contrai group (32 patients) receiving no immunoprophylaxis. Twelve months after surgery, 73% of ali the patients 100" ..
......, \ \
80" .. di S t~ 0.01).
~
\ \
pilflt ! nl ~
( j(}" ..
4() " ..
\
\ \ \
~ ... ..... .............
·-----------------·
/() ".
6
12
18
24
30
36 montl1 s
210
INTERNATIONAL JOURNAL OF DERMATOLOGY
pared to more than 40 months in patients without node involvement After 2 years, only 30% of patients . who initially had node involvement were stili free of recurrences, compared to 87% in cases without initial node involvement.
Aprii 1979
Vol. 18
pathological processes in which immune mechanisms are significant.
Drug Names nitrogen mu stard: Mustargen tetrami sol e: Ripercol tri-eth ylene-imino-benzoquinon: Trenimon
References Discussion Summarizing the results of our study, one must conclude that BCG given according to our schedule did not benefit patients in surgical remission of Stage l and Il malignant melanoma. Our results unfortunately did not confirm those reported from various other centers. 14 Presently, we have a new study under way utilizing a different treatment schedule and higher doses. For classification of melanomas we employ the histologic criteria according to Clark, 15 but also consider the actual thickness of the primary melanoma as proposed by Breslow. 16 We hope the results this time will be more favorable. The successful experience with BCG therapy in many centers has led to the search for similar vaccines with the advantages of BCG, but without its disadvantages. Corynebacterium parvum, treated with aqueous solution of formaldehyde is an alternative agent to BCG. 17 Use of chemical adjuvants such as tetrahydrophenylimidazo-thiazole hydrochloride (levamisole and tetramisole) avoids any complication s adherent to the use of microorganism s. Levami sole and tetramisole, initially used as anthelminthics, proved to be potent immunostimulants.18 Although showing some promise, tumor immunotherapy is stili in the primary stages of its development, providing a challenging area for investigation of the complexities of delicately balanced immunologie systems. lt may stimulate progress in fundamental aspects of immunology such as the biology of mononuclear cells, the role of noncellular mediators and their regulatory mechanisms, and may provide information relevant to infectious di sea ses and oth er norm al and
l. Nadler, S. H ., M oore, G. E. : lmmunotherapy of malignant di sease. Arch. Surg. 99 :376, 1969. 2. Neidhart, ). A., and Lobuglio, A. F.: Tran sfer-factor therapy of malignancy. Sem. Oncol. 1:379, 1974. 3. Lobu glio, A. F. .and Neidhart, ). A.: Transfer-factor: a pot enti al agent for ca ncer therapy. M ed. Cl in . North Am . 60 :585, 1976. 4 . Pilch, Y. H ., Frit ze, D ., and Dern , D . H .: Immune RNA in the immunotherapy of cancer. M ed. Clin . North Am. 60:567, 1976. S. Goldstein, A. l. , Cohen, G. H., Ross io, ). l. , et al. : Use of th ymosin in th e treatm ent of prim ary immunodeficiency diseases and ca ncer. Med . Clin . North Am. 60 :591 , 1976. 6. Kl ein, E.: Tumors of the skin : lmmunotherapy of cutaneou s and mucosa! neoplasm s. NY State ]. Med . 68 :900, 1968. 7. Kl ein , E. : Local cysto stati c chemoth erapy and immunotherapy. Geriatrics 23 : 154, 1968. 8 . Kl ein , E. Holtermann , O . A., Helm, F., et al. : Immunologie approac hes to the management o f primary and second ary tumors involving the skin and soft ti ssues: revi ew of a terì-year program . Transplant. Proc. 7:297, 1975. 9. Kl ein, E.: lmmunotherapeutic approaches to skin ca ncer. Hosp. Pract. 107, 1976. 10. Helm , F., and Kl ein, E.: Effect s of all ergie cont aci d ermatiti s on ba sa i c e li epith e liom as . Arch . Dermatol. 91 : 142, 1965. 11 . Bast, R. C. , Zbar, B., Borsos, T.,et al. : BCGand ca ncer. N . Engl. ). M ed. 290:1413, 1974. 12 . Aun gs t, C. W ., Sok al, ). E., and Jage r, B. V. : Compli ca tion s of BCG vaccinati on in neopla sti c d isease. Ann . lntern . M ed. 82: 666, 197 5. 13 . Sparks, F. C. : Haza rd s and complicati ons of BCG immunotherapy. M ed . Clin . North Am . 60:499, 1976. 14. Morton , D . L, El ber, F. R., Holmes, E. C., et al. : BCG immunotherapy as a systemic adjun ct to surgery in malignnt melanomas. M ed. Cl in . North Am. 60 :431, 1976. 15 . Cl ark , W. R., l r., From, )., Bernardino, E. A., et al. : The histo genesis and bio logica! beha vior of prim ary human malignant melanomasofthe skin. Cancer Res. 29 :705, 1969. 16. Breslow, A.: Tumor thickness, leve! of invasion and node dissection in stage l cutaneous melanoma . An n. Surg. 182 :572 , 1975. 17 . O ett ge n , H . F., Pin sky, C. M. , Delmonte, L.: Trea tment of ca ncer with immunomodulators. M ed. Cl in . North Am. 60:511 , 1976. 18. Sprea ii co, F. , Vecchi , A ., M antovani , A. , et al. : Ch arac teri za ti o n of th e immun os timul ant s levami sole and tetramisole. Eur. ). Cancer 11 :555 ; 1975.
INTRODUCTION TO TUMOR IMMUNOTHERAPY
FREDERICK HELM, M.D. , F.A.C. P. ANO JUTA HELM, M .D .
From the D epa rtm ent of Dermatology State University of New York Schoo / 0 { Medicine, Buffalo, New York
. The goal of eaneer immunotherapy is to alter Immune responses of the host to the tumor, enabling th e host to eliminate neoplast ie cells. Animai experiments and trials of imrnunotherapy in humans show that in prineiPie this is feasible. Unfortunately, tumor imrnunotherapy is stili in the preliminary stage, and mueh work remains to be done before it can attain the status of routine treatment. There are different approaches to imrnunotherapy (Table 1). In speeifie immun?therapy, the immune response of an indiVIduai is stimulated against his tumor. In nonspeci fi e immunotherapy, the antitumor effect re su lts from a nonspeeific enhanee~ent of immunoresponsiveness. In active lmrnunotherapy, antigens from the tumors (vaccines of whole tumor eells or subcellular components) are used to stimulate antibody Production. In passive immunotherapy, adrninistration of antitumor antibodies or tran sfer of sensi tized lymphocytes or their Produets, lymphokines, is utilized . A prerequisite for sueeessful immunotherapy is the immunoeompeteney of the patient. Cl in-
ieal assessment of immunoeompetenee ean
be accomplished with a series of standard skin tests outlined in Tabl e 2. lmpaired immunoeompetenee in pati ents with progressive malignant _di s~ase. is a bad prognostie sign. Results of m v1tro Immunologie tests sueh as lymp~oc_yt~. stimulation , maerophage migratlon _mhtbltlon, humoral antibody titration and 1mmunoglobulin levels do not seem to show a significant eorrelation with progression of the malignant di sease. Present evidenee indiea tes th at the immu~ o log ie defense of the host against his ~a!Jgna~ey ean be strengthened by inereastng the Immunologie responsiveness of-the host, inereasing the immunogenieity of the tumor eells, eliminating factors inhibiting the confrontation between lymphocytes and tumor ce lls, and by decreasing the tumor mass by surgery or ehemotherapy .
Specific Adoptive lmmunotherapy At Roswell Park Memoria! lnstitut e, Nadler
Presented at the XV lnternati onal Congress of Derrn atology, M exico City, Mexico, October 19, 1977. Address for reprints: Frederick Helm, M.D., Departrnent of Dermatology, Roswell Park Memoria! lnstitute, 666 Elm Street, Buffalo, NY 14203. 0011-9059/79/ 0400/0205 / $00.80
~nd Moore 1 tried to utilize specifie adopt ive
1mmunotherapy by cross immunizing pairs of pati ents with osteogenie sa reo ma s and
© lnternational Society of Tropical 205
D erm atology, lnc.
206
INTERNATIONAL JOURNAL OF DERMATOLOGY
Table 1.
Active
Vol. 18
Different Types of lmmunolherapy Nonspecific (lmmunopotentiators)
Specific
l
Aprii 1979
With sterilized tumor cells or tumor extracts
Contaci allergens: Trenimon, DNCB
Tumor cells treated with neuraminidase
Microorganisms and their products : BCG, Corynebacterium parvum, Vaccinia Chemical adjuvant s: Levamisole
Il
111
Passive
Antitumor sera obtained from animals immunized with fragments of patients tu mor patients whose tumor had undergone spontaneous regression and whose serum contains antibodies to the neoplasm
Transfer of immunologie active products from an immune donor
Adoptive
Tran sfer of allogenic or xenogenic immune lymphocytes
PHA stimul ated lymphocytes
Transfer factor lmmuno-RNA
melanomas. They cross transplanted their tumors and subsequently exchanged their sensitized peripheral blood lymphocytes. Unfortunately, immunization of patient A with tumor from patient B induced a response to transplantation antigens (HLA). Thus, the subsequent administration of lymphoid cells from patient A to the sensitized patient B led to a rapid destruction of the transfused cells and rarely showed the desired beneficiai effect. There is no evidence that the patients reacted to tumor antigens by forming specific antibodies to the neoplasm. The design of these experiments has been criticized and they have been abandoned. Some of the disadvantages of specific, passive immunotherpy with allogenic lymphocytes can be avoided by using immunologically active celi-free extracts of lymphoid celi products such as the transfer factor, 2• 3 and immune RNA. 4 • 5 lnjections of transfer factor, a low molecular weight extract of leukocytes, can be used to transfer delayed hypersensitivity. This method of treatment is successfully used in chronic mucocutaneous candidiasis and leprosy. The major problem
with the use of the transfer factor and immune-RNA for immunotherapy is lack of easy availability. Norma! subjects have been used as donors, because some may have had a tumor rejected and thus have an immunity to the tumor. Thymus extracts have also been used for immunotherapy. 5 Nonspecific Active lmmunotherapy
A form of nonspecific active immunotherapy for skin tumors has been introduced by E. Klein. 6 - 9 Delayed hypersensitivity reactions at tumor sites following active nonspecific stimulation are used. 6 - 9 In 1964, we reported that some tumors of the skin seem to be exquisitely sensitive to delayed hypersensitivity reactions, much more than the uninvolved skin. This was observed in a patient with multiple superficial basai celi carcinomas treated with tri-ethylene-imino-benzoquinon . 10 As soon as he became sensitized and developed a delayed hypersensitivity reaction, regression of his tumors at the site of the reaction was noted . After these observations, we used other contact allergens in a trial of immunotherapy of tumors involving the sk in. lmmu ~ nocompetency of the patient was established
No. 3
TUMOR IMMUNOTHERAPY
Table 2.
Helm and Helm
Assessment of T Ce li Function
PPD
Purified protein derivative of Mycobacterium tuberculosis (tuberculin).
V arida se®
Antigenic preparation of certain strains of streptococci. Mumps virus extract: this is an indicator of immunologie memory for childhood immunizations or infections. Candida albicans extract (positive in approximately 40% of immunocompetent patients).
Mumps vaccine Candida antigen Trichophyton
Extract of common dermatophytes.
Blastomycin
Blastomyces dermatitidis extract. The organism is found throughout North America . However, because less than l% of the population are positive reactors, blastomycin is a good contro! for negative reaction .
Histoplasmin
Histoplasma caps u/atum antigen skin tests are frequently positive in persons from the southeast regions of the United States. Coccidiodes immitis antigen skin tests are commonly positive in persons from the southwest regions of the United States. Dinitrochlorobenzene (DNCB), used to determine ability to respond to new antigens.
Coccidiodin
DNCB Trenimon
207
2, 3, 5 triethylene-imino-1 ,4 benzoquinone. This compound was used for the same purpose as DNCB. To Assess 8 Celi Fun ction
Testing is done with: Schick antigen
Corynebacterium diphtheriae toxin . The toxin produces necrosis in nonimmune or severely compromised patients. (more than 95% of the population neutralize the toxin).
and then delay hypersensitivity reactions were produced at the tumor. sites. Antitumor effects of the celi mediated hypersensitivity reactions were demonstrated clinically and by seria! biopsies. Tri-ethylene-imino-benzoquinon, dinitrochlorobenzene (DNCB) and nitrogen mustard were employed not only for treatment of severa! type of epidermal cancers and adenocarcinomas of the breast and melanomas but also for malignant lymphomas, esp~cially mycosis fungoides and histiocytic lymphoma. The immunologie reactions produced were independent of the tumor, which was iust an innocent bystander of an immunologie reaction. lt is therefore questionable if such an àpproach merits the classification of immunotherapy. The tumor regression may just have been the result of inflammation at the tumor site, rather than any specific immunologie process directed against tumor antigens. Nevertheless, it must be said that use of primary irritants, for instance, croton o il and burns produced with an ultraviolet lamp,
did not show the striking results seen with the use of tri-ethylene-imino-benzoquinon. The microorganism most widely used in tumor immun'otherapy has been Bacillus Calmette Guerin (BCG), which was obtained through progressive attenuation of a virulent strain of Mycobacterium bovis. 11 So far, the greatest experience has been gained in its use in malignant melanomas and lymphomas. BCG or PPD have been used in the treatment of a variety of cutaneous tumors, occasionally causing tumor regression. Table 3 outTable 3.
BCG Dose Schedule
Oral BCG was given 40 mg per week, 4 times 40 mg per month, 5 times 40 mg every 2 months, 6 times 40 mg every 6 months, 2 times BCG intradermally was given 0.1 mg per week, 4 times 0.15 mg per month, 5 times 0.2 mg every 2 months, 6 times 0.25 mg every 6 months, 2 times
208
Aprii 1979
INTERNATIONAL JOURNAL OF DERMATOLOGY
-- -·----·----•--.--
100"..
---------·
~
------~-6
80 ",, fr ee
40" ..
20" ..
6
12
18
24
30
Vol. 18
Fig. l . Di sease-free interval by sex. Broken fine indicates female pati ents (21); solid fine indicates mal e patients (46). Difference statisti ca lly significantly (p > 0.05).
36 months
d 1sease fr ee 1nt e rval
lines the BCG dosis schedule given to our malignant melanoma patients. Side effects were seen in 40% of our patients receiving BCG by injection or scarification. Fortunately, they were usually mild and included local complications as pruritus, induration, ulceration , BCG lupus, and regional lymph node enlargement. Systemic complications including fever, malaise, chills, vomiting, myalgia, arthralgia, progression of tumor growth, and erythema nodosum were seen occasionally. Vitiligo, uveitis, thrombocytopenia, anaphylactic reaction and death were not observed by us, but have been reported in the l iterature.I2,I3 100" •.
so·· .. d 1St!ilSt.~ lrPt !
''
''
''
Results of BCG lmmunotherapy
The clinica! data of this study were evaluated by the Computer Research Section of Roswell Park Memoria! lnstitute in Buffalo. Life table analysis was done using the Cutler and Ederer !ife table method . Between january of 1972 and December of 1976 immunoprophylaxis (Table 3) was used for Stage l and Il malignant melanoma patients at Rosewell Park Memoria! lnstitute in Buffalo, New York. Sixty-seven persons participated in this study (46 males and 21 females; 21 were under the age of 45, and 46 were over 45 years old). Forty-eight patients had Stage l
·~--------------------,,, >,
p c \tlt ! nt ~
•
'',,, '• 40 '· ·
20 '··
12
l
8
24
d1sease fr ee 1nterva l
30
36 month s
Fig. 2. Disease-free interval by age . Broken fine indicates patients over 45 years old (46); solid fine indicates patients under 45 years o Id (21 ). Difference statistically not significant (p> 0.05).
No. 3
-- -·----·----·----·----.
100"•o
------
---._
80°•o d1 sease
fr ee patlents
Fig. 3. Di sease-free interva l after prophylactic node dissection (Stage l malignant rnelanoma) . Broken line indicates patients without node dissection (26); solid line indicates patients with node dissection (22). Difference statistically not significant (p > 0.05).
209
Helm and Helm
TUMOR IMMUNOTHERAPY
6
12
18
24
30 months
d1sease fr ee 1nt erval
were clinically free of melanoma; after 24 months 70% and after 36 months only 59% . As observed by others, our study confirmed that women with malignant melanoma have a better prognosis than men (Fig. l). Our study comparing patients below and over the age of 45 did not show differences of the disease-free interval depending on age (Fig. 2). Prophylactic node dissection (no clinically ·enlarged palpable lymph nodes) d id not prolong the disease free interval after surgery (Fig. 3). As exp~cted, the disease free interval was much shorter in patients with node involvement (Fig. 4) . The median disease free interval in this group was 5.7 months com-
and 19 patients had Stage Il malignant melanoma. Nineteen received BCG orally and 16 intradermally; 32 melanoma patients were used as controls and remained without immunotherapy. We utilized a strain of living bovine tubercle bacilli (Bacillus Calmette Guerin) provided by the Connaught laboratories in Willowdale, Ontario, Canada. The disease-free interval for patients with Melanoma l (48) and Il (19) after surgery did not differ significantly between the BCG (35 patients) and the contrai group (32 patients) receiving no immunoprophylaxis. Twelve months after surgery, 73% of ali the patients 100" ..
......, \ \
80" .. di S t~ 0.01).
~
\ \
pilflt ! nl ~
( j(}" ..
4() " ..
\
\ \ \
~ ... ..... .............
·-----------------·
/() ".
6
12
18
24
30
36 montl1 s
210
INTERNATIONAL JOURNAL OF DERMATOLOGY
pared to more than 40 months in patients without node involvement After 2 years, only 30% of patients . who initially had node involvement were stili free of recurrences, compared to 87% in cases without initial node involvement.
Aprii 1979
Vol. 18
pathological processes in which immune mechanisms are significant.
Drug Names nitrogen mu stard: Mustargen tetrami sol e: Ripercol tri-eth ylene-imino-benzoquinon: Trenimon
References Discussion Summarizing the results of our study, one must conclude that BCG given according to our schedule did not benefit patients in surgical remission of Stage l and Il malignant melanoma. Our results unfortunately did not confirm those reported from various other centers. 14 Presently, we have a new study under way utilizing a different treatment schedule and higher doses. For classification of melanomas we employ the histologic criteria according to Clark, 15 but also consider the actual thickness of the primary melanoma as proposed by Breslow. 16 We hope the results this time will be more favorable. The successful experience with BCG therapy in many centers has led to the search for similar vaccines with the advantages of BCG, but without its disadvantages. Corynebacterium parvum, treated with aqueous solution of formaldehyde is an alternative agent to BCG. 17 Use of chemical adjuvants such as tetrahydrophenylimidazo-thiazole hydrochloride (levamisole and tetramisole) avoids any complication s adherent to the use of microorganism s. Levami sole and tetramisole, initially used as anthelminthics, proved to be potent immunostimulants.18 Although showing some promise, tumor immunotherapy is stili in the primary stages of its development, providing a challenging area for investigation of the complexities of delicately balanced immunologie systems. lt may stimulate progress in fundamental aspects of immunology such as the biology of mononuclear cells, the role of noncellular mediators and their regulatory mechanisms, and may provide information relevant to infectious di sea ses and oth er norm al and
l. Nadler, S. H ., M oore, G. E. : lmmunotherapy of malignant di sease. Arch. Surg. 99 :376, 1969. 2. Neidhart, ). A., and Lobuglio, A. F.: Tran sfer-factor therapy of malignancy. Sem. Oncol. 1:379, 1974. 3. Lobu glio, A. F. .and Neidhart, ). A.: Transfer-factor: a pot enti al agent for ca ncer therapy. M ed. Cl in . North Am . 60 :585, 1976. 4 . Pilch, Y. H ., Frit ze, D ., and Dern , D . H .: Immune RNA in the immunotherapy of cancer. M ed. Clin . North Am. 60:567, 1976. S. Goldstein, A. l. , Cohen, G. H., Ross io, ). l. , et al. : Use of th ymosin in th e treatm ent of prim ary immunodeficiency diseases and ca ncer. Med . Clin . North Am. 60 :591 , 1976. 6. Kl ein, E.: Tumors of the skin : lmmunotherapy of cutaneou s and mucosa! neoplasm s. NY State ]. Med . 68 :900, 1968. 7. Kl ein , E. : Local cysto stati c chemoth erapy and immunotherapy. Geriatrics 23 : 154, 1968. 8 . Kl ein , E. Holtermann , O . A., Helm, F., et al. : Immunologie approac hes to the management o f primary and second ary tumors involving the skin and soft ti ssues: revi ew of a terì-year program . Transplant. Proc. 7:297, 1975. 9. Kl ein, E.: lmmunotherapeutic approaches to skin ca ncer. Hosp. Pract. 107, 1976. 10. Helm , F., and Kl ein, E.: Effect s of all ergie cont aci d ermatiti s on ba sa i c e li epith e liom as . Arch . Dermatol. 91 : 142, 1965. 11 . Bast, R. C. , Zbar, B., Borsos, T.,et al. : BCGand ca ncer. N . Engl. ). M ed. 290:1413, 1974. 12 . Aun gs t, C. W ., Sok al, ). E., and Jage r, B. V. : Compli ca tion s of BCG vaccinati on in neopla sti c d isease. Ann . lntern . M ed. 82: 666, 197 5. 13 . Sparks, F. C. : Haza rd s and complicati ons of BCG immunotherapy. M ed . Clin . North Am . 60:499, 1976. 14. Morton , D . L, El ber, F. R., Holmes, E. C., et al. : BCG immunotherapy as a systemic adjun ct to surgery in malignnt melanomas. M ed. Cl in . North Am. 60 :431, 1976. 15 . Cl ark , W. R., l r., From, )., Bernardino, E. A., et al. : The histo genesis and bio logica! beha vior of prim ary human malignant melanomasofthe skin. Cancer Res. 29 :705, 1969. 16. Breslow, A.: Tumor thickness, leve! of invasion and node dissection in stage l cutaneous melanoma . An n. Surg. 182 :572 , 1975. 17 . O ett ge n , H . F., Pin sky, C. M. , Delmonte, L.: Trea tment of ca ncer with immunomodulators. M ed. Cl in . North Am. 60:511 , 1976. 18. Sprea ii co, F. , Vecchi , A ., M antovani , A. , et al. : Ch arac teri za ti o n of th e immun os timul ant s levami sole and tetramisole. Eur. ). Cancer 11 :555 ; 1975.
