Saturday, May 11, 2013
Peptide vaccines do NOT trigger effective immune reponse to melanoma!!!! Of mice and men....
Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion.
Hailemichael, Y, et al. Nat Med. 2013 Apr;19(4):465-72. Epub 2013 Mar 3. (Out of MD Anderson)
To understand why cancer vaccine-induced T cells often do not eradicate tumors, we studied immune responses in mice vaccinated with the gp100 melanoma peptide in incomplete Freund's adjuvant (peptide/IFA) [peptide vaccines like the ones I was given] which is commonly used in clinical cancer trials. Peptide/IFA vaccination primed tumor-specific CD8 (+) T cells, which accumulated NOT IN TUMORS but rather at the persisting, antigen-rich VACCINATION site. Once there, primed T cells became dysfunctional and underwent antigen-driven, interferon-y and Fas ligand mediated apoptosis [cell death], resulting in hyporesponsiveness to subsequent vaccination. Provision of CD40-specific antibody, [another] agonist and interleukin-2 reduced T cell [death] but did not prevent vaccination-site sequestration. A non-persisting vaccine formulation shifted T cell localization toward tumors, inducing superior antitumor activity while reducing systemic T cell dysfunction and promoting memory formation. These data show that persisting vaccine depots can induce specific T cell sequestration, dysfunction and deletion at vaccination sites; short-lived formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines.
Activation, dysfunction and retention of T cells in vaccine sites after injection of incomplete Freund's adjuvant, with or without peptide.
Salerno, EP, et al. Cancer Immunol Immunotther. 2013 May 9 [epub ahead of print] (Out of the University of Virginia)
We conducted a randomized clinical trial in 45 patients with...stage 11B-IV melanoma to characterize cellular and molecular events at sites of immunization with incomplete Freund's adjuvant (IFA) [the horrifying "thick white glue" component of my vaccines] alone, or a melanoma vaccine in IFA [what I got]. At a primary vaccine site, all patients received a multi-peptide melanoma vaccine in IFA. At a replicate vaccine site, which was biopsied, group 1 received IFA only; group 2 received vaccine in IFA. Lymphocytes....from the vaccine site microenvironments were compared to time-matched peripheral blood mononuclear cells.... Compared to [peripheral cells], the [cells from the vaccine sites] had fewer naive and greater proportions of effector memory CD8+ T cells. ....[W]ith a concentration of antigen-specific cells in the [vaccine site], particularly in ...sites with peptide (group 2) [aka ME!!!]. T CD8+ retained in the [vaccine sites] of both groups were strikingly dysfunctional, with minimal IFN-y production in response to peptide stimulation... These data suggest that vaccine-induced selective retention and dysfunction of antigen-specific TCD8+ within [vaccine sites] may represent a significant mechanism underlying transient immune repsonses and low clinical response rates to peptide vaccines administered in IFA.
In mice and men, when vaccinated with the plain medium, aka glue (Freund's adjuvant) or with the adjuvant combined with a peptide....like the vaccines I was given....the "rattie" will develop lots of primed tumor-specific T cells at the site. BUT...two problems!!!! The T cells freak out so much, that they become dysfunctional, often die, AND they continue to remain at the vaccine site, RARELY making it to the tumor cells they are supposed to be going after!!!
Pretty awesome, huh? So, the folks in my cohort had to endure 6 incredibly painful injections every two weeks for 6 months in alternating thighs. Not only that, while the vaccine and nasty glue did, perhaps, induce a response in T cells drawn to the sites (including the contralateral site...given the horrifying redness, warmth and swelling that would re-flare each time I was given more vaccines in the opposite leg), that response, more than likely...given the results of the mice and men above...was sequestered in the vaccine site ONLY. Now, we are left with lumpy legs, that may improve, but will never be the same. It is also conceivable, that T cells that could have been working against our tumors, were "wasted" and made unavailable to the immunologic effects of our simultaneous anti-PD1 infusions. Hopefully this is not true, as our numbers don't look much different from the original anti-PD1 ratties. Additionally, Brent is still considering that whatever trigger the vaccines may have provided, it may have played some role in my development of vitiligo. Another downside, is that these non-effective vaccines caused many people to be rejected from my trial because they did not have the appropriate HLA typing. In better news, currently there are many more arms for my anti-PD1 trial that require fewer or NO vaccines. I suppose researchers may work to create yet another vaccine with a "short-lived formulation" that could produce the desired response in T cells who would then get off their tookus and go out into the "world" to seek their fortune, actually attacking melanoma.
Ahhhh, the life of a rattie. I don't know about you....but I've had about all of the sequester I can take!!! - c