Extensive experience with isotransplants of 27 different tumours (leukaemias, sarcomata, carcinomata), all of strictly spontaneous origin in laboratory bred mice of low cancer strains CBA/Ht and WHT/Ht, has revealed no evidence of tumour immunogenicity. Of approximately 20,000 maintenance transplants, none failed and none regressed; of almost 10,000 carefully observed tumours arising from small or minimal inocula of tumour cells, none spontaneously regressed. The number of injected viable tumour cells required to give a 50% probability of successful transplantation (the TD50) ranged from approximately 1 cell to greater than 10,000 cells among the 27 tumours; high TD50 values, which were dramatically reduced by various procedures having no immunological significance, did not signify active "resistance" of the hosts. In the case of all of 7 randomly selected tumours, prior "immunization" of recipients with homologous lethally irradiated cells increased their tumour receptivity. Several experiments using various tumours failed to give evidence that immunity could be non-specifically induced or that a massive preponderance of lymphocytes from specifically sensitized mice could inhibit tumour transplantation or growth in vivo; no trace of "resistance" to tumour was adopted by isogeneic recipients of lymphocytes from regional nodes of tumour bearers. A limited review of the recent literature on tumour immunity shows that practically all the animal data presented in support of a general theory of tumour immunogenicity or to provide a basis for active clinical immunotherapy have been obtained from transplanted tumour systems which entail artefactual immunity associated with viral or chemical induction of the tumours or their allogeneic transplantation. It is suggested that isotransplants of spontaneously arising tumours are the only appropriate models of human cancer and that any genuine rapport between the animal laboratory and the clinic requires their exclusive use.

Summary.-Fully quantitative isogeneic transplantation assays of viable (V) cells of a CBA carcinoma showed that the relationship between log inoculum and frequency of tumour " takes " accorded strictly with a Poisson distribution and indicated that 6900 cells were required for 50%o takes (TD50 IF a sufficient number of viable tumour cells (V cells) are transplanted into an appropriate recipient animal, a tumour will develop. Revesz (1956) showed that if a large inoculum of V cells is accompanied by lethally irradiated (LI) cells of the same tumour, the resulting tumour develops earlier and reaches a lethal size earlier than in the absence of LI cells. This effect (the Revesz effect) was confirmed by Scott (1957), and extensive subsequent work has been reviewed by Revesz (1971).The Revesz effect has been shown to occur with a large number of tumours, both those in which immune reactivity of host against tumour can be demonstrated and those in which it cannot. The effect requires some local association between V cells and LI cells, for if the LI cells are given into the animal's opposite flank no stimulation results. In an irradiated tumour any surviving cells will be intimately mixed with lethally irradiated cells, so that the Revesz effect may be important in clinical radiotherapy as well as in the interpretation of survival curves obtained in vivo (see Hewitt and Wilson, 1961).

THE obvious structural and functional interdependence of normal tissue stroma and malignant cells in solid tumours persuaded the earliest radiobiological investigators that the effect of ionising radiation on these composite structures was the resultant of separate damage to the normal and malignant tissue components. It is understandable that, with a persistent inability to quantitate separately the damage to either component, unlimited scope prevailed for the assertion of rival theories in which the response of a tumour was attributed preferentially to direct damage to one or other component. Histological study of irradiated experimental tumours is of very limited value in assessing the contribution of direct stromal damage. This follows from the fact that direct damage to blood vessels is not readily distinguishable from changes consequent on the regression of stroma which must be expected to follow the dissolution of tumour cells whose reproductive integrity has been directly damaged by the irradiation.Recent developments in the quantitative radiobiology of mammalian tumour cells irradiated in vivo have encouraged interpretations of tumour response which refer, often exclusively, to the direct effect of radiation on the clonogenic cell population of the tumour. Such exclusive consideration has undoubtedly been proved to be justified in respect of the relation between the estimated size of a tumour cell population in a tumour and the single dose of radiation required for its cure under specified conditions of oxygenation. This relation has been found to accord with the predictions of relevant radiation survival curves (Hewitt, 1963;Reinhold and De Bree, 1966), this last information being obtained under conditions where stromal changes make no contribution. Suit, Shalek and Wette (1964) conclude from their extensive dose-cure studies of murine adenocarcinoma that their results " do not indicate a tissue effect on cellular radiosensitivity, tumour bed effect on tumour curability, or non-specific host-tumour effect ".If, as it appears, radiation-induced damage to the stroma makes no measurable contribution to the eradication or " cure " of a tumour, the question remains whether such damage influences the character of the changes of tumour volume which are brought about by irradiation of a tumour in vivo. The consideration achieves particular importance when attempts are made to interpret tumour regrowth curves in terms of survival curves for the clonogenic tumour cells. Thomlinson and Craddock (1967) state that, for the rat fibrosarcoma they studied, the oxygen enhancement ratio determined from measurements of the growth response of their tumours to irradiation is considerably greater than that obtained from in vitro studies of the clonogenic cells of their tumour. They refer to capillary damage as possibly conducing to the discrepancy. Several reports have appeared of the volume response of tumours to a single or fractionated dose of

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A squamous cell carcinoma of spontaneous orgin in a WHT/Ht mouse was used to study the frequency with which the regional axillary lymph nodes draining subcutaneous or intradermal tumours gave rise to tumours after their isogeneic transplantation as whole nodes. This frequency (similar to 40%) was found not to vary significantly with the size or duration of the tumour drained and not to be increased by coincident infective, traumatic or antigenic stimuli acting at the tumour site or in adjacent tissue. Because tumour growth occurred in only 2/55 (4%) nodes which were left in situ in mice whose tumours were radically excised, it was concluded that tumour forming node transplants reflected a small and limited content (estimated to be about 13) of transnodally passing tumour cells destined to pass on to the blood; separate experiments showed that tumour cells reaching the blood survived for only a few hours. Nodes from tumour-excised mice gave rise to tumours as frequently when autografted as when isografted to mice with no previous expose to the tumour. A review of the finding reported here and of previous quantitative data for this system enabled us to exclude any implication of anti-tumour immunity from our interpretation of the results of the experiments.