|Melanoma blood vessel|
Designing tumor vaccines presents a bunch of problems that anti-pathogen vaccines don’t. One of those problems is identifying an appropriate antigen. There’s been a lot of interest in finding tumor antigens that cytotoxic T lymphocytes will recognize, and in fact hundreds have been identified. The database of tumor antigens at Cancer Immunity lists some 750 of them, divided into various categories:
- Unique antigens result from point mutations in genes that are expressed ubiquitously. They are unique to the tumor of an individual patient or restricted to very few patients;
- Shared tumor-specific antigens are expressed in many tumors but not in normal tissues;
- Differentiation antigens are also expressed in the normal tissue of origin of the malignancy;
- Overexpressed antigens are expressed in a wide variety of normal tissues and overexpressed in tumors
Overall, shared tumor-specific antigens may be the ideal target. Because they’re found in multiple tumors, a vaccine can be pre-designed and go through a time-consuming optimization and validation process; because they’re only found in tumors, there’s less concern about safety. That is, the risk of the vaccine precipitating an autoimmune reaction to normal cells is low.
|MHC expression in eye
before and after vaccination
The problem with this class is that there just aren’t all that many tumor-specific antigens. The database lists 20-odd such antigens, and many of them are only found in a limited subsets of tumors (mostly melanomas). What’s more, I think it’s not merely that the targets are out there yet haven’t been identified. More likely, there simply are not many shared tumor-specific antigens.
The next-best category, as far as safety and effectiveness is concerned, is the unique antigens. These may be great as far as safety and effectiveness are concerned, but there are major technical problems in identifying them in a clinical context. Because they’re unique, you can’t pre-design the vaccine; you need to customize the antigen to each patient. And (at least with present techniques) by the time there is enough tumor available to look for unique antigens, the disease is likely to be pretty far advanced (and advanced tumors are more likely to be resistant to vaccination, for several reasons). There’s a lot of interest in making preparations of tumors that would contain unique antigens, without the trouble of identifying the antigen, but as far as I know that hasn’t made it very far into clinical trials yet.
So that leaves overexpressed and differentiation antigens. These are both, by definition, found in normal cells, and that means either the immune system is already tolerized to the antigen, or that targeting these antigens with a vaccine risks triggering an autoimmune reaction.
In fact, clinical trials using these kinds of vaccines against melanomas have found that successful tumor attack is almost invariably associated with an autoimmune effect, usually manifesting as vitiligo (de-pigmented patches on the skin).
It is expected that immune responses to such peptides will be compromised by self-tolerance or, alternatively, that stimulation of effective immune responses will be accompanied by autoimmune vitiligo. 1
I believe the first record of this goes back to 1964.2 Vitiligo is not, as autoimmune diseases go, a terrible problem, and certainly one would be delighted to trade melanoma for vitiligo. However, there are more serious potential problems as well, and one of them was recently reported by Nick Restifo’s group. 3 In this case, a highly active anti-melanoma vaccine not only killed the tumor, it also triggered severe autoimmune destruction of the eye; and the more effective the vaccine, the worse the autoimmune disease:
Thus, in the present model, the efficacies of the antitumor immune therapies were directly correlated with the induction of autoimmunity in the eye. … Our data suggest that, as tumor immunotherapies improve, these autoimmune manifestations may become more prevalent.
(My emphasis.) The autoimmune disease in these melanoma patients is still probably manageable (they mention using 30 months of steroid treatment in one of the most severely affected patients), and even if not, again the tradeoff is one most people would probably take (blindness vs. death). But other tumors may make the decision much more difficult:
Although the autoimmune side effects of melanocyte/melanoma-targeted therapies have been manageable, the unintended autoimmunity of therapies targeting colorectal, brain, or lung cancer might prove more severe.
- Antigens derived from melanocyte differentiation proteins: self-tolerance, autoimmunity, and use for cancer immunotherapy. Engelhard VH, Bullock TN, Colella TA, Sheasley SL, Mullins DW. Immunol Rev. 2002 Oct;188:136-46. [↩]
- Vitiligo In A Case Of Vaccinia Virus-Treated Melanoma. Burdick Kh, Hawk Wa. Cancer. 1964 Jun;17:708-12.[↩]
- Palmer, D.C., Chan, C., Gattinoni, L., Wrzesinski, C., Paulos, C.M., Hinrichs, C.S., Powell, D.J., Klebanoff, C.A., Finkelstein, S.E., Fariss, R.N., Yu, Z., Nussenblatt, R.B., Rosenberg, S.A., Restifo, N.P. (2008). From the Cover: Effective tumor treatment targeting a melanoma/melanocyte-associated antigen triggers severe ocular autoimmunity. Proceedings of the National Academy of Sciences, 105(23), 8061-8066. DOI: 10.1073/pnas.0710929105 [↩]