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ARTICLES
Year : 1982  |  Volume : 30  |  Issue : 4  |  Page : 327-332

Cancer therapy-an immunological approach


Institute of Ophthalmology, A.M. U. Aligarh, India

Correspondence Address:
R Gogi
Institute of Ophthalmology, A.M.U. Aligarh
India
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Source of Support: None, Conflict of Interest: None


PMID: 6984694

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How to cite this article:
Gogi R, Johri A. Cancer therapy-an immunological approach. Indian J Ophthalmol 1982;30:327-32

How to cite this URL:
Gogi R, Johri A. Cancer therapy-an immunological approach. Indian J Ophthalmol [serial online] 1982 [cited 2020 Aug 4];30:327-32. Available from: http://www.ijo.in/text.asp?1982/30/4/327/29464

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Immunotherapy of cancer is an exciting and rapidly developing field. Over the past twenty years a burst of immunologic know­ledge has appeared and with it a new science of "Tumour Immunology" has emerged. Investigations of immunolgical reactions against cancer cells now make an active field of cancer research. It is the blessing of cancer immunology that a new branch of immuno­therapy for the treatment of human cancer has come up. Most, and probably all types of cancer in man are associated with tumour. Specific antigens are capable of producing an immune response. This capacity is shared by tumours of the eye and its adnexae. In the present paper it is the purpose to introduce some of the principles of cancer immunology, as we know them now, and to discuss the principles of immunotherapy in controlling the malignancy. Most of the clinical informations available have been derived from cases of mali­gnant melanoma, which is a popular hunting ground for immunotherapists.


  Basic concept Top


Human lymphoid system has mainly two types of lymphocytes, that is T-lymphocytes (Thymus dependent lymphocytes) and B-lymphocytes (Bursa dependent lymphocytes) T-lymphocytes are responsible for cell media­ted hypersensitivity or delayed hypersensitivity or cellular immunity. These cells liberate

chemically active substance known as lympho­kine. Whereas B-lymphocytes are antibody forming cells and are responsible for humoral immunity. Both B and T-cells produce an immunological reaction on exposure to a foreign protein.


  Tumour antigen Top


Normal host cells may undergo a somatic mutation and malignant cells are formed, alter­natively there may be reversion of tumour cells to the state of embryonic phase when embroynal antigens are present. These abnor­mally formed cells differ from healthy cells and are, therefore, antigenic. Tumour antigens (neoantigens) are present either on cell mem­brane which can induce a cell mediated response, or, though rarely, antigen may be present in the cytoplasm of the malignant cell and is called cytoplasmic antigen. Circulating lymphocytes are unable to make contact with the intracytoplasmic antigens of intact tumour cells. Thus immunological response to cyto­plasmic antigens can develop only if there is cell degeneration. These tumour antigens stimulate Both B and T-lymphocytes.


  Tumour growth and immune response Top


Normally a major part of the host immune response is concerned with the recognition and elimination of malignant cells and cancer develops when this surveillance becomes defec­tive. This is supported by the observation that malignant disease is usually prevalent in patients undergoing prolonged immuno suppressive therapy during homograft trans­plantation' and in individuals with congenital deficiency of lymphoid tissue.[2] It has also been observed that cell mediated immunity to a variety of antigens is depressed in patients with malignant disease[3].

In a normal individual tumour proteins are recognised as `Foreign' and there is a predomi­nant T-cell response leading to destruction of malignant cells. But this does not always happen and the tumour keeps on growing. This may either be due to depressed immuno­logical response or there may be delay in T-cell response because the initial small number of tumour cells are unable to provide sufficient antigenic stimulus. By the time this mechanism become operative the tumour has already crossed the critical safe period[4]. Thus it is the immunological behaviour of the individual that determines subsequent course of the malignant neoplasm. It has been repeatedly stressed that tumour gets an opportunity to grow either in the presence of an auto-immune disorder or as a result of immune competition between B and T-cells response. Under normal circumstances normal tissue proteins are recog­nised by the lymphoid system and there is no immunologic response. When a normal tissue protein is recognised as foreign protein this results in an auto-immune disease. However, there is another auto-immune disorder when an abnormal tumour protein is recognised by the lymphoid system as & Self', therefore, the tumour is not rejected by the lymphoid system and it persists.

Immune competition concept, infact, makes the real basis for immunotherapy in malign­ancy. According to this the tumour antigens stimulate both B and T-cells. T-cell response proves cytotoxic towards the tumour cells lead­ing to tumour destructions. In response to B-cell stimulation there is formation of anti­bodies (1gG & IgM) which get coated on the malignant cells[5],[6]. Since these are `Blocking antibodies' therefore, malignant cells after getting its coating cannot be destroyed by the fragments may combine with antibodies to make complexes which in turn get coated on the sensitized T-lymphocytes and thus prevent­ing the T-cells to be effective. Hence it infers that T-cells deal with tumour destruction[7] and B-cells promote tumour proliferation[8]. The kinetics of cell response of these two popula­tions of lymphocytes will determine the pro­gression or remission of the malignant process, Humoral response can also play some role by causing necrosis due to complement dependent antibody response.


  IMMUNO-THERAPY IN MALIGNANCY Top


Keeping the basic concept of cancer immunology in mind the immunotherapy can be summarised as follows :­

Immunotherapy of cancer is directed in two directions, that is, (1) Immuno-inhibitory methods and (2) Immuno-stimulatory methods.

Immuno-inhibitory methods :

Immuno-inhibitory methods deal in keep­ing control on "Blocking-antibodies". Once these antibodies have been knocked out the surface coating malignant cells will be no more there and T-lymphocytes are free to exercise the process of tumour destruction. This can be achieved either by suppression of formation of `Blocking antibodies' that is, suppression of B-lymphocyte growth or by elimination of blocking antibodies. B-lymphocytes can be suppressed by administration of anti B . lymp­hocyte antisera and antiplasma cell antisera. Blocking antibodies can be eliminated by plasmapheresis etc. [Table - 1]

Immuno-stimulatory methods

Immuno-stimulation can be achieved by supplying new immuno-competent T-lympho­cyte to the patients[6]. Passive transfusion of lymphokines has also been attempted. Active immunization of the patient using puri­fied tumour antigen, or non-viable tumour cells or a modified tumour antigen has been reported to be quite helpful(10). A non-specific T-cell stimulation can be conveniently carried out by using Di-nitrochlorobenzene BCG, Corynebac­trium parvum etc[7] as shown in the [Table - 2]. These stimulants potentiate the macrophage and reticuloendothelial system. The clinical application of this method is adjuvant like and is more convenient than other sophisticated procedures. Thus these agents enhance the immune response and their presence evokes a high order immune response and may thus help the patient out of this incurable crises.

This new subject although fascinating yet it has its own limitations. It can not eradicate large tumour masses and, therefore, it cannot replace, at present, the classical surgical, radio­therapeutic or chemotherapeutic methods. However, it offers a useful role when the classi­cal treatment fails, that is, it can destroy small deposits of malignant cells which are responsi­ble for secondary metastases and recurrences. However, a combine immuno and chemother­apy can be more fruitful.


  Materials and methods Top


All the cases of intraocular and adneral tumours attending A.M.U. Institute of Ophthalmology were subjected to various immunological tests. The present study will include 20 cases of histologically proved cases of malignancy. The status of their delayed hypersensitivity response (T-lymphocyte res­ponse) was determined with the help of Dini­trochloro-benzene (DNCB) (supplied by BDH, England). The test technique is basically the same as described by Catalona et al (1972). In selected cases T-lymphocyte stimulation was carried out.


  Dncb screening test technique Top


Two solutions of DNCB, solution A (20%) a stronger solution and solution B(0.5%) a weaker solution, were prepared. Flexor surface of forearms of both sides were cleansed with aceton and 10 microlitres of solution A (Con­taming 2 mg. of DNCB) was allowed to evaporate over a 10mm area of skin of right arm, acetone evaporates leaving behind DNCB. Similarly, 10 microlitres of solution B(.05mg of DNCB) was applied on left arm. All subjects were examined daily for a minimum period of . 16 days and the reactions were scored on 14th­16th days. The quantitative method was employed for scoring as shown in [Table - 3]. The results of this screening test in various malignant lesions has been shown in [Table - 4].


  T-LYMPHOCYTE STIMULATORY METHOD Top


Principal of this treatment is that DNCB is a chemical that stimulates thymus derived, i.e. T-lymphocytes exclusively. There is an increase in the T-lymphocyte population thereby promo­ting the tumour fighting capacity of the individual.

For T-cell stimulation, 17 cases showing 2+, 1+ and anergy to DNCB were taken. These cases included uniocular retionablas­toma (9 cases), squamous cell carcinoma of limbus (2 cases), Basal cell circinoma of lid (2 cases), secondary orbital tumours (2 cases) and one case each of orbital rhabdomyosar­coma and adenoid cystic carcinoma of lacrimal gland. A dose of 50mg. of DNCB near the test site was applied every month for two turns and reaction was studied similarly. Care was taken that patients do not take steroids during tcsting and stimulation schedule.


  Control Top


DNCB screening test was carried out in 75 normal volunteers belonging to different age groups. Similarly DNCB screening test was carried out in 26 cases belonging to different benign neoplastic lesions of lid, conjunctiva and orbit.


  Results and comments Top


DNCB screening test showed that out of 20 cases of malignancy, 17 cases showed either poorly positive or anergy to DNCB as shown in [Table - 4]. It was found that 25% of the cases were completely anergic to DNCB as compared to normal control or benign lesions where percentage of total anergy was only 2% and Zero percent respectively (Data of normal population and various ocular disorders is under publication). A high incidence of anergy or poor responsiveness to DNCB indicates that malignant disease influences the host immune response and this is a call for urgent immuno­logical help to the patient. Using the same technique poor responsiveness to DNCB in cases of general body cancer has been reported as high as 60% (Catalona et al, 1971). Thus we selected 17 cases showing 2+, 1 + or anergy to DNCB test. Amongst the nine cases of retinoblastoma, only four came for check with a follow up varying from two to five months. Other cases did not come for check and is very difficult to comment upon it. Other cases of lid, conjunctiva and orbital malignancy have a follow up of six to eight months except in one case of metastatic orbital lesion who did not survive. It is important to point out that the standard surgical treatment and radiotherapy was carried out in every case. The present treatment is only a supportive therapy in conjunction to surgery and radio­therapy. Further this is only a preliminary report and we hope to provide more details as the follow up study of more cases adds up in the years to follow. The purpose of this communication is to introduce and to encour­age the immunotherapy simultaneously along­with surgical radiotherapeutic and or chemo­therapeutic management of various malignant lesions of eye and its adnexal.


  Summary Top


Basic concept of immunotherapy in cancer has been introduced.

Technique for DNCB screening test and T-lymphocyte stimulation has been described.

A preliminary report on our clinical finding has been included.[12]

 
  References Top

1.
Doak P. B2, Montgomerie J.Z., Norih J.D.K. and Smith F., 1968 , Brit. Med. J. 4 : 746.  Back to cited text no. 1
    
2.
Fraumeni J F., 1969 , Nat, Cancer Inst. Mono­graph, Haemopictic Neoplasma., 32:221.  Back to cited text no. 2
    
3.
Harris, J.E. and Binkovics J.G., 1970, The Immunology of Malignant Disease, Mosby, St. Louis.  Back to cited text no. 3
    
4.
Old L.J., Boyse E.A., Clarke D.A. and Carswell F.A., 1962, Ann. NY Acad. Sci., 101 : 64.  Back to cited text no. 4
    
5.
Kaliss N., 1962, Ann. NY Acad., Sci., 101 : 64.   Back to cited text no. 5
    
6.
Moller G., 1962, J. Nat. Cancer Inst. 30 : 1177.  Back to cited text no. 6
    
7.
Piessens W.F., 1970, Cancer, 26: 1212.  Back to cited text no. 7
    
8.
Taylor, G. and Odili J.L., 1970, Britt. J. Cancer, 24 : 447.  Back to cited text no. 8
    
9.
Mathe G., 1970, Brit. Med. J., 4 : 487.  Back to cited text no. 9
    
10.
S. Jogren H.O., Hellstronii., Bansal S.C. and Hellstrom K.E., 1971, Proc. Nat. Acad, Scs. U.S.A., 68 : 1372.  Back to cited text no. 10
    
11.
Old. I., Clarke D.A, and Benacerraf B. 1959, Nature 184: 291.  Back to cited text no. 11
    
12.
Catalona, W.J., Taylor, P.T., Rabson, P.T, and Chreiien, P.B., 1972, New Engl. J. Med. 286: 399,  Back to cited text no. 12
    



 
 
    Tables

  [Table - 1], [Table - 2], [Table - 3], [Table - 4]



 

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  In this article
Basic concept
Tumour antigen
Tumour growth an...
IMMUNO-THERAPY I...
Materials and me...
Dncb screening t...
T-LYMPHOCYTE STI...
Control
Results and comments
Summary
References
Article Tables

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