XVivo: Cancer cell attackAlthough 750-odd tumor antigens may seem like quite a few potential vaccine targets, it’s really not so much when you’re dealing with billions of individual tumors; and so when designing a tumor vaccine, you may have to make some compromises. The peptide may bind to the MHC class I with low affinity, for example, making it relaitvely non-immunogenic. Several groups who are working on tumor vaccines have tried to work around this problem by optimizing tumor antigens in various way, hoping to boost the immunogenicity while retaining the specificity of the peptide. This has often seemed to work quite nicely, cranking up immune responses significantly while keeping the response focused on the tumor. Nevertheless, a recent study1 suggests that this may not be a good idea.

Melanomes (Wellcome)It has been suggested2 that cancer antigens tend to be poor MHC binders. That would mean that the peptide falls out of the MHC complex relatively rapidly and becomes invisible to T cells, so that to keep a certain level of target on the cell surface, you’d need to start with much more; in other words, the peptide would be less immunogenic. (This has been explicitly shown for a number of tumor epitopes, but as far as I know has not been globally demonstrated. It occurs to me that the Immune Epitope Database [IEDB]   may have enough information to at least make a start at that analysis; maybe I’ll take a run at it, in whatever of my  free time isn’t taken up by playing baseball with my fanatic son.)

If the natural peptide doesn’t bind stably to MHC, perhaps an analog peptide — a peptide with a slightly different amino acid sequence — can be made, with the same T cell recognition properties, that does bind well; and this analog could be used for immunization. That’s just what has been done in a number of clinical trials,3 and the results have actually looked good; for example, mice immunized with an analog peptide of a melanoma tumor antigen generated far more T cells than with the natural antigen. 4

But bigger is not always better, and now Speiser et al. have examined the effects of an analog peptide qualitatively as well as quantitatively. Again using a melanoma antigen, they compared  the immune response to a natural and an analog peptide vaccination. As with other studies, the analog peptide induced more T cells; about twice as many. But the quality5 of the T cells induced by the natural peptides was much better, to the point that the less abundant natural response, was more effective in its anti-tumor function than the more abundant response induced by the analog peptides.

At first, it seems paradoxical that the “less immunogenic” natural peptide induced more strongly functional T cells. … CD8 T cells must be able to recognize low amounts of viral peptide antigen for protection. More recently, in vivo experiments in mice showed that the peptide concentration used for DC labeling and priming inversely correlated with the avidity of TCRs of memory cells. Thus, one may conclude that vaccination should be done with low peptide doses and/or peptides with low HLA binding stability (provided that one can still elicit a reasonably strong T cell response).

(My emphasis.)  This is actually strikingly reminiscent of some of the recent work on viral — especially HIV — immune responses, where T cell quality (induction of “multifunctional” T cells) seems to be more important than maxing out the number of T cells. 6.  I guess it’s not surprising that the anti-cancer and anti-viral responses are similar in this, as they are in many other ways.

  1. Speiser, D.E., Baumgaertner, P., Voelter, V., Devevre, E., Barbey, C., Rufer, N., Romero, P. (2008). Unmodified self antigen triggers human CD8 T cells with stronger tumor reactivity than altered antigen. Proceedings of the National Academy of Sciences, 105(10), 3849-3854. DOI: 10.1073/pnas.0800080105[]
  2. For example: Poor immunogenicity of a self/tumor antigen derives from peptide-MHC-I instability and is independent of tolerance. Zhiya Yu, Marc R. Theoret, Christopher E. Touloukian, Deborah R. Surman, Scott C. Garman, Lionel Feigenbaum, Tiffany K. Baxter, Brian M. Baker, and Nicholas P. Restifo. J Clin Invest. 2004 August 16; 114(4): 551-559. doi: 10.1172/JCI200421695. []
  3. Speiser et al. cite a half dozen instances; I won’t parrot them[]
  4. Parkhurst et al. (1996) Improved induction of melanoma-reactive CTL with peptides from the melanoma antigen gp100 modified HLA-A*0201-binding residues. J Immunol 157:2539-2548. []
  5. Quality in this case means functional ability to deal with the cancer; it includes things like activatability, amount of cytokine production, and amount of lytic proteins produced[]
  6. For example: Induction of multifunctional human immunodeficiency virus type 1 (HIV-1)-specific T cells capable of proliferation in healthy subjects by using a prime-boost regimen of DNA- and modified vaccinia virus Ankara-vectored vaccines expressing HIV-1 Gag coupled to CD8+ T-cell epitopes. Goonetilleke N, Moore S, Dally L, Winstone N, Cebere I, Mahmoud A, Pinheiro S, Gillespie G, Brown D, Loach V, Roberts J, Guimaraes-Walker A, Hayes P, Loughran K, Smith C, De Bont J, Verlinde C, Vooijs D, Schmidt C, Boaz M, Gilmour J, Fast P, Dorrell L, Hanke T, McMichael AJ. J Virol. 2006 May;80(10):4717-28. and references therein.[]