I have been researching and writing about vaccines as a treatment for melanoma for over 8 years. (Here's a collection of vaccine posts if you're interested:
All about those vaccines!!!) Matter of fact, the inclusion of a peptide vaccine in my Phase 1 MDX-1106 (then BMS 936558, then nivolumab, then Opdivo!!!) trial, back in 2010, was a big part of the draw! Sadly, the peptide vaccine component did us no good:
Peptide vaccines do NOT trigger effective immune reponse to melanoma!!!! Of mice and men.... Despite no grand success with vaccines for melanoma in all these years, I still hold out hope that they can become, if not a cure, then at least a valuable component in the way we treat melanoma.
To back up a step, what is a vaccine anyway???? Thanks to Edward Jenner, Louis Pasteur, and Joseph Lister we learned about GERMS! ~ how they attack our body and how our body deals with them!!! Simply put, a vaccine is a dab of the germ or something like it, that is injected into our body in order to teach our immune system to recognize it as bad, mobilize against it, and kill it if it ever invades our sanctum again!! For instance, when folks were dying and being scarred for life from small pox, Jenner noted that the chicks who milked the cows, and had previously suffered from the similar but less deadly and devastating disease cowpox, did not catch smallpox. So, he used a smidge of cow pox goo, placed into a small scrape in the skin, to "vaccinate" folks against small pox. It worked!!! Today we use similar principles, including dead or "attenuated" versions of some germs, to create vaccines against a wide variety of diseases. When it comes to cancer vaccines there are a couple of sorts. Some cancers are known to be caused by oncoviruses. So vaccines we use for Hep B and HPV work against the virus pretty much as noted above. In cancer vaccines that we think about for melanoma we can use the
proteins from cancer cells themselves to trigger an immune response, in hopes of having our immune system kill the actual cancer. Another method, actually uses oncolytic viruses to trigger an immune response in the area of our melanoma. This is pretty much what talimogene laherparepvec (T-VEC, also called Imgylic) does by using a specially engineered herpes virus to express GM-CSF and aid the immune system in responding to tumor antigens. Clear as mud? Okay.....I think we are ret tah go!!!
A
novel immunization strategy using cytokine/chemokines induces new
effective systemic immune responses, and frequent complete
regressions of human metastatic melanoma. Valentine, Golomb, Harris,
Roses.Oncoimmunology.
2017 Oct 30.
Immune
responses have been elicited by a variety of cancer vaccines, but
seldom induce regressions of established cancers in humans. As a
novel therapeutic immunization strategy, we tested the hypothesis
that multiple cytokines/chemokines secreted early in secondary
responses ex-vivo might mimic the secretory environment guiding new
immune responses. The early development of immune responses is
regulated by multiple cytokines/chemokines acting together, which at
physiologic concentrations act locally in concert with antigen to
have non-specific effects on adjacent cells, including the maturation
of dendritic cells, homing and retention of T cells at the site of
antigen, and the differentiation and expansion of T cell clones with
appropriate receptors. We postulated that repeated injections into a
metastasis of an exogenous chemokine/cytokine mixture might establish
the environment of an immune response and allow circulating T cell
clones to self- select for mutant neo-epitopes in the tumor and
generate systemic immune responses. To test this idea we injected
some metastases in patients with multiple cutaneous melanoma nodules
while never injecting other control metastases in the same patient.
New immune responses were identified by the development of dense
lymphocytic infiltrates in never-injected metastases, and the
frequent complete regression of never-injected metastases, a
surprising observation. 70% of subjects developed dense infiltrates
of cytotoxic CD8 cells in the center and margin of never-injected
metastases; 38% of subjects had complete and often durable
regressions of all metastases, without the use of check-point
inhibitors, suggesting that, as a proof-of-principle, an immunization
strategy can control advanced human metastatic melanoma.
Here a chemokine/cytokine mixture (juice to fire up the base and get those t-cells fighting mad) was injected directly into a melanoma tumor, in the same way intralesionals are. Just like intralesionals (Here's a link to everything you never thought you'd want to know about those: INTRALESIONALS.) patients developed increased numbers of CD8 cells around injected and non-injected lesions. Also like other intralesional therapies, some injected lesions went away and through a by-stander response some lesions that had NEVER been injected also disappeared! In the final analysis, "38% of subjects had complete and often durable regressions of all metastases". Obviously, this response is not a bad thing!! BUT, "often durable regression" is not very clear and a 38% response rate, if it holds in further testing, is no better that anti-PD-1 alone. And since this vaccine was NOT administered with a systemic therapy....what if you did? We have found in other intralesionals that the response improves with simultaneous use of systemic therapy.
To that end, there's this:
Dendritic
cell vaccine induces antigen-specific CD8+ T cells that are
metabolically distinct from those of peptide vaccine and is
well-combined with PD-1 checkpoint blockade. Nagoaka, Hosoi, Lino,
et al. Oncoimmunology.
2017 Nov 2.
The
success of immune checkpoint blockade has unequivocally demonstrated
that anti-tumor immunity plays a pivotal role in cancer therapy.
Because endogenous tumor-specific T-cell responsiveness is essential
for the success of checkpoint blockade, combination therapy with
cancer vaccination may facilitate tumor rejection. To select the best
vaccine strategy to combine with checkpoint blockade, we compared
dendritic cell-based vaccines (DC-V) with peptide vaccines for
induction of anti-tumor immunity that could overcome tumor-induced
immunosuppression. Using B16 melanoma and B16-specific TCR-transgenic
T-cells (pmel-1), we found that DC-V efficiently primed and expanded
pmel-1 cells with an active effector and central memory phenotype
that were not exhausted. Vaccine-primed cells were metabolically
distinct from naïve cells. DC-V-primed pmel-1 cells contained the
population that shifted metabolic pathways away from glycolysis to
mitochondrial oxidative phosphorylation. They displayed better
effector function and proliferated more than those induced by peptide
vaccination. DC-V inhibited tumor growth in prophylactic and
therapeutic settings. Only DC-V but not peptide vaccine showed
augmented anti-tumor activity when combined with anti-PD-1 therapy.
Thus, DC-V combined with PD-1 checkpoint blockade mediates optimal
anti-cancer activity in this model.
Here, in a petri dish, researchers treated melanoma cells with a dendritic vaccine and a peptide vaccine. They found that only the dendritic vaccine (NOT the peptide vaccine, further corroborating what we real live ratties found in my study) helped increase anti-tumor activity when combined with anti-PD-1 therapy. Okay. As far as that goes....
Now, there's this...
Cancer
vaccine formulation dictates synergy with CTLA-4 and PD-L1 checkpoint
blockade therapy. Hailmichael, Woods, Fu, et al. J Clin Invest. 2018 Feb 26.
Anticancer vaccination is a promising
approach to increase the efficacy of cytotoxic T
lymphocyte-associated protein 4 (CTLA-4) and programmed death ligand
1 (PD-L1) checkpoint blockade therapies. However, the landmark FDA
registration trial for anti-CTLA-4 therapy (ipilimumab) revealed a
complete lack of benefit of adding vaccination with gp100 peptide
formulated in incomplete Freund's adjuvant (IFA). Here, using a mouse
model of melanoma, we found that gp100 vaccination induced
gp100-specific effector T cells (Teffs), which dominantly forced
trafficking of anti-CTLA-4-induced, non-gp100-specific Teffs away
from the tumor, reducing tumor control. The inflamed vaccination site
subsequently also sequestered and destroyed anti-CTLA-4-induced Teffs
with specificities for tumor antigens other than gp100, reducing the
antitumor efficacy of anti-CTLA-4 therapy. Mechanistically, Teffs at
the vaccination site recruited inflammatory monocytes, which in turn
attracted additional Teffs in a vicious cycle mediated by IFN-γ,
CXCR3, ICAM-1, and CCL2, dependent on IFA formulation. In contrast,
nonpersistent vaccine formulations based on dendritic cells, viral
vectors, or water-soluble peptides potently synergized with
checkpoint blockade of both CTLA-4 and PD-L1 and induced complete
tumor regression, including in settings of primary resistance to dual
checkpoint blockade. We conclude that cancer vaccine formulation can
dominantly determine synergy, or lack thereof, with CTLA-4 and PD-L1
checkpoint blockade therapy for cancer.
So these peeps are back where I started!! Within the second link at the start of this tome, Peptide vaccines do NOT trigger effective immune reponse to melanoma!!!! Of mice and men....,
I wrote: 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. We knew that in 2013, guys!!! But, in 2018 we reiterate: one real potential problem with cancer vaccination can be to attract and trap our cancer fighting t-cells at the vaccine site, rather than allowing them to attack our tumors!!
But, now....straight out of ASCO- 2018!!!!....there is this:
Interim analysis of a prospective, randomized, double blind, placebo controlled, phase IIb trial of the TLPLDC vaccine to prevent recurrence in resected stage III or IV melanoma patients. Myers, Clifton, Hale ... Sussman ... George Earl Peoples. ASCO 2018.
The autologous tumor lysate, particle loaded, dendritic cell (TLPLDC) vaccine has been shown to be safe and immunogenic while producing objective tumor responses in a variety of metastatic patients (pts). Here, we present the pre-specified interim results of a randomized, double blind phase IIb trial assessing the TLPLDC vaccine to prevent recurrences in high risk melanoma pts. Methods: Stage III and IV resectable melanoma pts were identified prior to definitive surgery and consented for tumor collection. Pts were re-consented for treatment and randomized 2:1 (vaccine (V): placebo (P)). TLPLDC or placebo vaccines were initiated within 3 mos of completion of standard of care (SoC) therapies. Intradermal inoculations were given at 0, 1, 2, 6, 12, and 18 mos. Pts were followed for recurrence per SoC, and the primary endpoint is 2 yr disease-free survival (DFS). The interim was pre-specified at 6 mos from the 120th randomization. Survival analysis was performed on the intention-to-treat (ITT) and per treatment (PT) populations. The latter excludes early recurrences during the primary vaccine series (PVS) (up to 6 mos). Results: The trial randomized 120 patients (V = 83, P = 37). There were no clinicopathologic or treatment-related differences between the groups except for median age (V = 65 yrs, P = 57 yrs). There were 3:1 stage III:IV in both groups. Study-wide, only 33% of pts experienced treatment-related adverse events (AEs) with 98.6% being grade 1-2. There were no serious AEs or immune-mediated AEs. In the ITT analysis, there was no difference in recurrence at a median f/u of 11.9 mos. In the PT analysis, there was a trend toward decreased recurrences in the TLPLDC arm at a median f/u of 12.6 mos.
Conclusions: The TLPLDC vaccine is safe with minimal toxicity. Among pts completing the PVS period (6 mos), there is a strong trend toward fewer recurrences in the TLPLDC arm. This benefit will be confirmed at the primary analysis of 2 yr DFS; however, these early data provide an encouraging signal that a phase III trial for efficacy may be warranted. Clinical trial information: NCT02301611
So, if you look up this trial on Clinicaltrials.gov you will see that all these patients had to have enough melanoma to collect and make the vaccine from...and...if they were not rendered NED after that surgery they were disqualified...and...some were given Neupogen (G-CSF) and some were not. In the end, this is basically an adjuvant study. Are you confused yet??? Ultimately, they report a "trend" toward fewer recurrences????? Okay, Mr. Peoples, if you want those odds when you get melanoma, go right ahead. A vaccine that FAILS to demonstrate statistical significance doesn't have a place in MY treatment plan, even if you call the results of its use a "trend". Plus, you took out the recurrences in the first 6 months of the treatment!!!! "The latter excludes early recurrences during the primary vaccine series (PVS) (up to 6 mos)." I may have had melanoma brain mets, but I can still read!!! And with that HUGE exclusion, you STILL couldn't present statistically significant data!!!
Now, call me crazy ~ but long before the Russians, social media and whoever else you want to name, worked to influence our election and thought processes ~ I was taught to look closely at sources. Having been required to peruse medical research for my patients, myself, and my blog (ie for all you melanoma peeps out there) I find that it is essential to understand who is telling you what and why!!!!
So here is a bit of information on Mr. George Earl Peoples...
Today, if you check out
Perseus, Personalized Cancer Immunotherapeutics you will find this slick web site with amazing testimonials and a cover page that notes Dr. Thomas E. Wagner was a
"co-founder" of Perseus PCI, but NEVER tells us who the other co-founder was. Hmmm.... Just to make things a bit more interesting, another page from that site gives the "reasons" Perseus PCI
in the Cayman Islands (!!!???) is such a good idea! (And there's a blog!! With quotes from "Celeste"! Just so you know, that ain't me, y'all!!!) Hmmmmm....indeed!!!
Cue the
The Black Eyed Peas - Pump it!!! "Ha, HA, HAA - Pump it!!!" 'Cause when you look at
Elios therapeutics, LLC, you find the
"leadership" to be: Thomas Wagner, George Peoples, and Buddy Long, all grinning like the Cheshire Cat at the bottom of the page! Hmmm....
But, remember that Perseus PCI vaccine from Perseus in the Cayman's that noted only ONE co-founder??? Guess who was the other "co-founder" and promoter of that little Cayman Vacay!??
Orbis Health Solutions - Cancer vaccine in the Cayman Islands notes:
Under the direction of cancer vaccine pioneer Dr. George Peoples, the newly named chief medical officer of Orbis/Perseus, patients will be brought to Cayman for a series of injections that will be tailored to stimulate their immune system to recognize and destroy their specific tumor.
Dr. Peoples, who has helped to invent various other cancer vaccines while serving as the director of the Cancer Vaccine Development Program and deputy director of the U.S. Military Cancer Institute, was in Cayman this month along with Perseus president Buddy Long. He explained the significance of these new trials for cancer sufferers.
“Orbis, the parent company of Perseus in the United States, has undertaken 12 years of clinical research and trials under the approval and guidance of the Food and Drug Administration, part of an ongoing FDA process of approval to have our cancer vaccines available in the United States.
“This is a long and extremely costly process that involves various stages before the vaccine can receive FDA approval. Our cancer vaccine has passed the laboratory and animal stages and the first stage in patients, which is to prove that it is safe, and now we need to begin the second stage, to prove that the vaccine actually works,” he explained.
Cayman the right fit
Dr. Peoples and Mr. Long said they looked to other jurisdictions close to the United States that would provide them with a base to continue their clinical trials.
“As a mark of validation of our work, we were looking at jurisdictions with a strong regulatory environment because we want our data to be scrutinized,” Long said. “Cayman was the ideal location. We picked our location at the Smith Road Centre and had commenced construction of the lab and treatment facility even before we had the approval to begin our research by the local authorities; we were that committed to the program. Our studies all follow FDA guidelines and have full approval of the Health Practice Commission.”
In the United States, Perseus has treated 25 patients with stage IV melanoma (skin cancer) which had spread to other organs in the body. On average, these patients had been given eight months or less to live.
“After receiving the vaccine, these patients lived on average 14-1/2 months, and 27 percent were completely cured and alive greater than five years later. These statistics were enough to get people’s attention,” Dr. Peoples said.
“But we need a bigger trial to get the FDA approval required. In addition, technology has changed in recent years, and we need to incorporate that into our new trials.”
Hmmmm.....hmmmm....hmmmmm....
Here is some "data" Perseus presents on their site:
Cancer Treatment Trial Results Phase I/II Melanoma Personalized Cancer Vaccine Trial This data is presented in nifty graphs but is basically meaningless as it combines Stage I, II, III, and IV peeps all together!!!! As I wrote about a year ago,
"this is the consummate example of "fuzzy math". Stage I data combined with Stage IV???? If folks want to sign up...good enough. Just think you should be informed about what you are signing up for."
And last but not least, we have the venerable veteran George E. Peoples, noted to be the
Founder of Cancer Insight who with his great cancer knowledge and reputation as cancer expert (or charlatan and shell game master extraordinaire...you decide) is directly linked to a wide variety of institutions and Big Pharma.
It seems Perseus and Mr. Peoples have abandoned the Personalized Vaccine trial for the moment, so let's get back to the TLPLDC vaccine and data touted in the ASCO piece...
This particular report appears to be based on the preliminary results from the clinical trial using TLPLDC. Here 120 Stage III/IV melanoma patients with resected tumor (ie NED) were divided into 2 groups. 83 were given the dendritic vaccine. 37 were given placebo. An interesting point is that these peeps were 3:1 :: Stage III:Stage IV. Stage III is not defined, so we could be looking at mostly Stage 3a patients who have a fairly good prognosis without any further treatment - just say'n! There was no difference in recurrence in either group at a median f/u of almost one year. The report also notes that of the patients treated, "there was a trend toward decreased recurrences in the TLPLDC arm at a median f/u of 12.6 mos." Don't forget! This is the very group from which those who recurred in the first 6 months of treatment were EXCLUDED and with that, all you got was a "trend"???!!! Now, you could possibly argue that one needs 6 months to give the vaccine a chance to work. But 6 months in melanoma world is a long time, y'all!!!
Now...check out this report: AACR 2018 - Elios Therapeutics Presents Initial Phase 2b Results of TLPLDC, a Personalized Therapeutic Cancer Vaccine for the Treatment of Melanoma
Mr Peoples took 22 previously resected patients who recurred in his study - who may have already had the vaccine or not - it is not clear - and offered them an open label option. 7 were resected again and opted to take the vaccine TLPLDC. 1 of those recurred at 12.5 months. 15 of the 22, had non-resectable recurrences. 2 withdrew from the study. 1 opted for no further treatment. 12 got the vaccine plus standard of care (meaning their oncologist provided melanoma treatment). Of those 12: 2 attained a complete response at 8.6 months. 7 had stable disease. 2 had progressive disease. 1 had progressive disease that was converted to a complete response with the use of pembro. No times are provided for any of these.
People's grand pronouncement to this mess is: "TLPLDC vaccine after recurrence may have benefit when combined with SOC [standard of care therapy]
in the adjuvant setting and in patients with measurable metastatic disease."
Wow! Eating grape fruit MAY provide some benefit to folks with resected or advanced melanoma!!! These numbers are so small, and the variables are so scrambled, that the only thing I can extract from this "data" is the fact that Mr. Peoples has a group of desperate folks who agreed to take his vaccine. Things have not gone very well and at this point he is hanging on to THEM for dear life - letting them take anything and everything - and still - somehow - trying to tie it back to his TLPLDC vaccine. Maybe it's just me, but that's all I've got!!!
And with that supreme expenditure of my time and limited brain power...we start that saga of ASCO 2018!! I still hold out hope that vaccines will become beneficial for melanoma peeps. I certainly hope that ASCO 2018 will be filled with much more positive data and real help for melanoma patients. I will present the abstracts that seem important as they are written, with my "take" in red beneath. (And when I need to breathe, there may be some sewing posts squished in!!!)
Here we go!!!! - c
