TVAX Biomedical

In the 1950’s, Richard Prehn and Marjorie Main made the seminal observation that signaled the potential for cancer specific immunotherapy.  They demonstrated that cancers are immunogenic.  They used experimental animal cancers to demonstrate that the cancer bearing host's immune system sees cancer as foreign.  That observation raised the theoretical possibility that anti-cancer immune responses could be manipulated for therapeutic benefit.  Subsequent studies have demonstrated that most and probably all cancers are immunogenic. Glenn Dranoff and his coworkers subsequently demonstrated that even the least immunogenic cancers could induce an immune response if they were part of a sufficiently potent vaccine.

In the 1970's, immune T cells were shown to be responsible for cancer immunity.  Immune T cells then were shown to be able to kill cancer cells 'in test tubes'.  Those observations on underlying immune mechanisms raised the possibility that 'killer' T cells could be used as anti-cancer agents in the same way that cytotoxic drugs are used.  That is, 'killer' T cells could be delivered into the bloodstream of an individual with cancer and would travel to sites of cancer growth, enter cancer tissue and kill cancer cells.

In the 1980’s, Suyu Shu and his co-workers demonstrated that ‘killer’ T cells could reject growing cancers and cure cancer bearing animals.  'Killer' T cells were shown to produce their anti-cancer effects in the absence of any other form of treatment and could, at effective doses, produce permanent cures with no evident toxicity.

Several important observations have been made by Shu’s group and by many other groups of scientists during the ensuing decades.

1. "Killer" T cells have proven to be effective against all types of animal model cancers.  Unlike the situation with chemotherapies, no type of cancer has yet been shown to be resistant.  Since all available evidence points to the view that all mammalian cancers are immunologically similar, it is possible to hypothesize that "killer" T cells would be similarly effective against all types of human cancer.

2. Cancers were rejected wherever they were growing in the body.  It's not possible to produce experimental testing conditions in rodents that are identical to treating a naturally progressing human cancer, but the various experimental conditions that have been generated provide as close an approximation to the human condition as one can generate in rodent models of immunotherapy.

3. As would be predicted, since the effects were immunological, there was a direct relationship between susceptibility to "killer" T cells and the cancer's immunogenicity.

4. Unlike many cancer treatments, there invariably was a direct relationship between response rate and overall survival.  In all models tested, it was possible to produce permanent cures with no associated toxicity.

Extensive proof-of-principle studies were performed in brain cancer models before initiating human brain cancer studies.  Although, when those studies were initiated, it was widely believed that the 'blood-brain barrier' would protect brain cancers from immune attack, studies using several different brain cancer models demonstrated that T cells could kill cancer cells and permanently reject cancers growing in the brain.

These brain cancer studies were important for several reasons.  They demonstrated that brain cancer is susceptible to immunotherapy, something that had not been thought possible. They also demonstrated that an immunological treatment produced permanent cures even when the cancer was growing in a site as remote as the brain.  As proof-of-principle studies, they raised the possibility that the general treatment approach was directly translatable to humans with brain cancer, a prediction that proved to be true.

Outcomes obtained with brain cancer are important for brain cancer, but because brain cancer doesn’t spread outside of the brain – it doesn’t normally metastasize, these results aren’t necessarily applicable to cancers growing outside the brain.  Most cancers, regardless of tissue or organ of origin, have the capacity to spread to other body sites, e.g., to metastasize to other organs and tissues.  The studies that are most directly relevant to the potential susceptibility of those human cancers are all of the other studies that have been performed in animal models that demonstrated that killer T cells could effectively treat any kind of cancer growing in virtually any part of the body that cancer could be experimentally implanted. 

Two studies were performed specifically to determine whether killer T cells could effectively treat experimental cancers that had spontaneously metastasized to unknown sites distant from where the original cancer was growing.  In both of those studies killer T cells were shown to cure animals bearing extremely weakly immunogenic cancers that had spread to unknown body sites from a primary cancer. 

Cancer immunogenicity:

1.  Prehn RT, Main JM.  Immunity to methylcholanthrene-induced sarcomas. Journal National Cancer Institute. 18:769-7 (1957)

2.  Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine GM-CSF stimulates potent, specific, long-lasting anti-tumor immunity. Proceedings National Academy Science USA 90:3539-43 (1993)

Treating various cancers with killer T cells:

1.  Shu S, Chou T, Rosenberg SA. In vitro sensitization and expansion with viable tumor cells and interleukin 2 in the generation of specific therapeutic effector cells. Journal of Immunology. 136:3891-8 (1986)