|Year : 1982 | Volume
| Issue : 4 | Page : 327-332
Cancer therapy-an immunological approach
R Gogi, Anil Johri
Institute of Ophthalmology, A.M. U. Aligarh, India
Institute of Ophthalmology, A.M.U. Aligarh
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Gogi R, Johri A. Cancer therapy-an immunological approach. Indian J Ophthalmol 1982;30:327-32
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|| |
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|| |
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|| |
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. It has also been observed that cell mediated immunity to a variety of antigens is depressed in patients with malignant disease.
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. 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,. 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 and B-cells promote tumour proliferation. 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|| |
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-stimulation can be achieved by supplying new immuno-competent T-lymphocyte to the patients. 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 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|| |
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|| |
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|| |
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|| |
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|| |
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|| |
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.
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[Table - 1], [Table - 2], [Table - 3], [Table - 4]