Background Science

Haptens are tiny lights that illuminate the dark recesses of the immune system. They were discovered by Karl Landsteiner, who used haptens to explore the breadth and fine sensitivity of antibody responses. Landsteiner worked with a variety of simple chemicals, including nitrophenyls and phenyl arsonates, that were incapable of inducing an immune response by themselves, but became immunogenic when they were attached covalently to a protein carrier. He coined the term “hapten” from the Greek haptein, meaning to fasten.

As the physiology and biochemistry of T lymphocytes was elucidated, it became clear that hapten-modified proteins also elicited a T-cell response. Guinea pigs that were sensitized by topical application of 1-chloro-2,4-dinitrobenzene (DNFB) developed lymphocytes that proliferated when cultured with dinitrophenyl (DNP)-conjugated syngeneic lymphocytes. It was not possible to show that these DNP-reactive lymphocytes were T cells until the availability of antisera (against the so-called theta antigen) that specifically killed T cells. In a seminal and probably controversial paper, Rubin and Wigzell reported that DNFB-sensitized mice generated splenic and lymph node lymphocytes that provided help to B cells obtained from mice immunized with BSA when the readout was the in vitro production of antibody to DNP-BSA. These helper lymphocytes were, in fact, T cells, as demonstrated by absence of surface anti-IgM (immunoglobulin) and their sensitivity to anti-theta antibody. The same phenomenon could be demonstrated in the murine antibody response to murine serum albumin (MSA), but in this case the helper T cells were not specific for DNP but for the “new antigenic determinants” on MSA produced by the DNP conjugation.

There is considerable evidence that the failure of immunotherapy to eradicate cancers, whether spontaneous human cancers or experimental transplantable tumors, is a result of immunological tolerance. However, it was possible to break tolerance against the progressor tumor by haptenization. A number of other investigators demonstrated that modification of tumor cells with DNP or TNP increased the efficacy of vaccines. The most recent publication on the use of hapten modification for experimental immunotherapy is from Sojka et al. They used the highly metastatic 410.4 tumor that had originated from a spontaneous murine mammary carcinoma. The result was positive and highly reproducible: mice that received DNP-modified vaccine had significantly longer relapse-free survival than animals receiving the unmodified vaccine, which, incidentally, was no better than saline.



Berd D: Hapten-modified tumor vaccines.  In, Handbook of Cancer Vaccines, Editors: M. A. Morse, K. Lyerly, T. M. Clay,

Chapter 19: Hapten-Modified Tumor Vaccines, Totowa, NJ, Humana Press Inc., pp 275-296, 2003