Spleen Cells from Young but Not Old Immunized Mice Eradicate Large Established Cancers

Abstract

PurposeSolid tumors that have grown two weeks or longer in mice and have diameters larger than 1 cm are histologically indistinguishable from autochthonous human cancers. When experimental tumors reach this clinically relevant size, they are usually refractory to most immunotherapies but may be destroyed by adoptive T cell transfer. However, TCR-transgenic T cells and/or tumor cells overexpressing antigens are frequently used in these experiments. Here we studied the requirements for destroying clinical size, unmanipulated 8101 tumors by adoptive cell therapy.Experimental Design8101 arose in an old mouse after chronic exposure to UV light. A cancer line was established, which was never serially transplanted. The immunodominant CD8+ T cell-recognized antigen of this tumor is caused by a somatic tumor-specific mutation in the RNA helicase p68. 8101 tumors were treated with spleen cells from young naïve, or young and old immunized mice to ascertain the characteristics of immune cells that lead to rejection.ResultsHere we show that the mutant p68 peptide has an exceptionally high affinity to the presenting MHC class I molecule Kb and that spleen cells from immunized young syngeneic mice adoptively transferred to Rag-/- or cancer-suppressed euthymic mice eradicate 8101 tumors larger than 1 cm in average diameter and established for several weeks. Spleen cells from naïve young mice or from old and boosted (re-immunized) mice were ineffective.ConclusionsRelapse-free destruction of large and long-established tumors expressing a genuine very high-affinity tumor-specific antigen can be achieved by using adoptive transfer of lymphocytes from immunized young individuals.

Adjuvant cellular immunotherapy in patients with resected primary non-small cell lung cancer

“…45 Schreiber, et al also demonstrated that spleen cells from young but not old immunized mice could eradicate large established cancers. 46 Therefore, young patients with better immune function results show improved clinical outcome.…”

Targeting cancer-specific mutations by T cell receptor gene therapy

“…The retrospective analysis of melanoma patients responding to immunotherapy supports the data from experimental cancer models [2,53**]. A patient with a partial regression following anti-CTLA4 monoclonal antibody (mAb) treatment revealed a dominant CD8 T cell response against a mutant epitope [29*].…”

“…The same case can be made for the Darwinian selection of cancer cells lacking the rejection antigen by a regressor tumor transplanted into normal immunocompetent mice. Such a selection occurs in many different transplant settings [2,26,37,50]. Similar to the above-mentioned sporadic cancer model, T cells did not impair tumor development in a transposon-based autochthonous cancer model [51].…”

“…In contrast to therapeutic vaccinations, adoptive T cell therapy (ATT) can very effectively eradicate large, long-established tumors in mice [1,2,3**,4] and induce sustained regression in humans [5**,6**]. The grafting of new antigen specificity onto patients’ T cells by TCR gene transfer is widely applicable to target any antigen on the cancer cells.…”

Spleen Cells from Young Donors Eradicate Large Tumors–Letter

“…We have read with great interest the recent study by Schreiber and colleagues (1) in the May 1, 2012 issue of Clinical Cancer Research. This article elegantly uses a naturally induced tumor (8101 tumor) containing a mutated high MHC-binding epitope (p68) from RNA helicase as a target for adoptive cell therapy with tumor sensitized T cells from young or old mice.…”