Angelyn Rios

Immunotherapy of Cancer: Immunospecific Rejection of Tumors in Recipients of Neuraminidase-Treated Tumor Cells Plus BCG

Firmly established methylcholanthrene fibrosarcomas in syngeneic mice will totally disappear if the hosts are treated with living tumor cells that have been exposed to Vibrio cholerae neuraminidase in vitro. The effect is magnified by the simultanieous injection of a nonspecific immunostimulant, BCG. The rejection of the methylcholanthrene tumor is immunospecific and can be induced only with tumor cells, treated with Vibrio cholerae neuraminidase, identical in type with the growing tumor.

Cell surface modification in the treatment of experimental cancer: Neuraminidase or concanavalin a

Firmly established tumors in syngeneic mice will regress if the host is challenged with living tumor cells which have been exposed to Vibrio cholerae neuraminidase (VCN) or Concanavalin A (ConA) in vitro. The effect is totally immunospecific and can be induced only with VCN‐ or ConA‐treated tumor cells identical in type with the growing tumor. The degree of immunoregression is similar when using optimal concentrations of ConA and VCN. The fact that two such different substances can alter the cell surface to increase the immunogenicity of tumor antigens may shed some light on the mechanisms involved.

Regression of spontaneous mammary carcinomas using direct injections of neuraminidase and BCG

Abstract 1. 1. Vibrio cholerae neuraminidase (VCN) injected directly into spontaneous mammary adenocarcinomas will induce a slowing of tumor growth. 2. 2. BCG will induce a similar regressive effect. 3. 3. The combined intratumor injections with BCG and VCN will induce the total regression of some spontaneous mammary adenocarcinomas. By analogy with the effect of these agents in syngeneic transplanted tumors, the effect can be considered to be immunological. 4. 4. Additional mammary adenocarcinomas will develop in mice with regressing tumors possibly because the immunity induced by the intratumor injections of VCN and/or BCG is not directed to the MTV antigen but rather to weaker specific antigens on the treated tumor.

EXPERIMENTAL CANCER IMMUNOTHERAPY: MODIFICATION OF TUMOR CELLS TO INCREASE IMMUNOGENICITY

Firmly established transplantable C3H/HeJ mammary carcinomas can be inhibited by host challenge with Vibrio cholerae neuraminidase (VCN)-treated tumor cells. The effect is totally immunospecific, even VCN-treated tumors bearing shared mammary tumor virus (MTV) antigen cannot induce the regression. Thus, VCN is capable of increasing the immunogenicity of the private, unique-unshared tumor antigens on mammary carcinomas; VCN is incapable of increasing the immunogenicity of the shared MTV-associated tumor antigen even in syngeneic C3HeB/FeJ MTV-free mice. The immunoregressive effect of VCN-treated tumor cells can be augmented by subtotal or total surgical excision of large transplantable tumors. Spontaneous mammary tumors in retired breeder C3H/HeJ female mice can be made to regress by two immunological maneuvers: (1) repeated intratumor injections of VCN and/or BCG; and (2) total excision and immunotherapy with VCN-treated autochthonous mammary tumor cells. The use of VCN-treated transplantable mammary tumor cells sharing the MTV-associated antigen was not better than excision alone. The evidence supports the idea that active specific immunotherapy of spontaneous tumors with VCN-altered tumor cells may require the use of autochthonous cells.

Modification of Immunogenicity in Experimental Immunotherapy and Prophylaxis

Sialic acid residues are the principal constituents on the surface of plasma membranes [5] and make the chief contribution to the negative charge of the cell surface [1]. A number of functional alterations of the cell can be induced by removal of the sialic acid from the surface membrane by neuraminidase [7, 8, 10, 23]. These include enhanced phagocytosis [15, 31], inhibition of viral [4] or mycoplasma [11] induced hemagglutination, inhibition of cell aggregation [14], increased cell deformability [30], alterations in the patterns of cellular migration [32] and interference with amino acid transport across treated cell membranes [6]. Currie and Bagshawe [8] postulated that, because of their negative charges, the sialomucins on cells interfered with detection of cellular immunogens by lymphocytes. Apffel and Peters [2] have broadened this concept by suggesting that masking of antigens is one of the normal natural biological roles of glycoproteins, and that sialoglycoprotein on the cell surface may be a distinct system of immunoregulation. These hypotheses are supported by the finding of Sanford [23] that TA-3 tumor, which has lost strain specificity, would not kill recipient mice if the cells were treated in vitro with neuraminidase before i. p. inoculation. Independently, Currie and Bagsuawe [8] showed that neuraminidase-treated Landschutz ascites tumor cells, L 1210 leukemia cells [3], and methylcholanthrene-induced sarcoma cells [9] grew less well in normally susceptible mice. Recipients were subsequently shown to be immune to the tumor. Ehrlich’s ascites tumor was found [16] to be rendered more immunogenic when treated with neuraminidase before inoculation, and Currie et al. [10] also claimed that mouse trophoblast could be made to express histocompatibility antigens by treatment with neuraminidase. They suggested that these changes in immunogenicity were more likely to be attributable to an “unmasking” of antigens on cell surfaces than to changes in surface charge.