Phase I/II trial of PD1 antibody nivolumab with peptide vaccine in patients naive to or that failed ipilimumab

ASCO Abstract for 2013 annual meeting, J Clin Oncol 31, 2013, (9011)
Authors:  Weber, Kudchadkar, Gibney, et al.  Moffitt Cancer Center, Tampa, Florida

Nivolumab (new name for MDX 1106, then BMS 936558), an IgG4 human monoclonal antibody against checkpoint protein PD1, is active in metastatic melanoma, renal cell disease, and non-small cell lung cancer.  It was given with a multi-peptide vaccine to patients with unresectable melanoma who failed at least one regimen and were ipi naive or had failed ipi.

Three cohorts of 10 HLA A0201 positive, ipi - naive patients were given nivolumab at 1, 3, or 10mg/kg.  Three additional cohorts of patients who had failed prior ipi were given nivolumab at 3mg/kg:  2 of these cohorts with 10 patients each and were A0201 positive and had either grade 2 or less ipi toxicity, or grade 3 dose limiting ipi toxicity and were not HLA restricted.  Pretreatment archived tumor tissue, as well as pre and post-treatment peripheral blood cells were collected.

RESULTS:  Response rates by RECIST were 28% in 34 patients naive to and 32% for 46 patients who failed prior ipi.  Nivolumab did not induce the same irAEs (immune related adverse events) in patients with prior ipi induced toxicity. No cohort had more than one dose limiting toxicity. 2 patients had grade 3 pneumonitis.  Biomarker studies showed that elevated NY-ESO 1 and MART-1 specific CD8 T cells pre-treatment were associated with non-response, while CTLA-4 positive CD4T cells and T regulatory cells were elevated after treatment in non-responders.  Immunohistochemical analysis of pre-treatment tumors indicated that PD-L1 staining was associated with response, but responses were also observed in patients whose tumors did not stain.

CONCLUSIONS: Objective responses to nivolumab were observed after ipi and to ipi after failing nivolumab. Elevation of CTLA-4 after nivolumab in non-responders suggest that sequential therapy with the combination should be tested.  Tumor PD-L1 was associated with but not predictive of response.

MY THOUGHTS:
1.  This is my study...though my cohort...Stage IV NED metastatic melanoma patients...is not included in this data, though we were treated with the same vaccines and the same three dosing groups of 1, 3, or 10mg/kg doses of nivolumab.  (See my post from March 22, 2013.  Where I noted my best assessment of results for my cohort:  In my NED group:  N = 31. Seven patients progressed while in the trial. Two patients have passed.  One is probably going to pass soon. Of the 4 remaining that progressed, 2 are subsequently NED again (I cannot tell you if this is with additional treatment or without.  I know from past conversations one patient had become NED after initially progressing with NO treatment and I know that other patients had been "doing well" with subsequent treatment with ipi....however, I do not know what was done in these two cases in particular.)  THEREFORE....now, of the original 31 patients, 26 remain NED.  That demonstrates a clinical benefit of 83%.  Dr. Weber admitted that is was "much better" than he had ever thought we would do.  He said he was meeting with the folks at BMS to try to set up a trial with anti-PD1 as a real adjuvant treatment for melanoma patients with resected disease today...given these results.  Additionally, a proposal for publication of at least some of the data from my trial has been submitted for discussion/presentation at ASCO in June.  Whether either of these things will really happen remains to be seen.)  Apparently, the data from my cohort has been accepted for presentation at ASCO.  Hopefully, I will have more to report after my trip to Tampa in June.


2.  See my post on September 9, 2012 for my thoughts on testing our tumors for PD-L1 staining.  Wonder if any of us ratties will ever be privy to that intel or to the story our CD8 T cell pre and CD4 T and T reg cells post infusions told.

3.  See my more recent post, May 11, 2013, documenting the results of two studies which indicate that the peptide vaccines utilized in many of the patients in both the NED and unresectable groups DID ABSOLUTELY NOTHING OF BENEFIT!!!!!!!!!!!!! Though the requirement of HLA typing for A0201 did keep many patients OUT of the study!


4.  Nivolumab?  That's the name?  Really????????????????????  What the tub?

It's a mighty rattie world out there - c

4 year survival rates for patients with metastatic melanoma who received ipilimumab...

...in Phase II clinical trials.
By: Wolchok, Weber, Maio, Neyns, Harmankaya, Chin, Cykowski, de Pril, Humphrey, Lebbe'
Ann Oncol. 2013 May 10 [Epub ahead of print].  Source:  Memorial Sloan Kettering.

Abstract synopsis:  This analysis was carried out to evaluate long term survival of patients with metastatic melanoma who received ipilimumab (ipi), a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4 in clinical trials.

Patients were given ipi in one of three completed Phase II trials.  Previously treated patients as well as those who were treatment naive were included.  Patients were given ipi at a dose of 10mg/kg in 2 studies and at doses of 0.3, 3, or 10mg/kg in another. Ipi was given every 3 weeks for 4 doses, eligible patients could receive ipi maintenance therapy every 12 weeks. In one study, patients could cross over to be retreated with ipi at 10mg/kg upon disease progression.  Ongoing survival follow-up is being conducted in a companion study.

RESULTS:  Four year survival rates for previously treated patients who were given ipi at 0.3, 3, or 10mg/kg = 13.8%, 18.2%, and 19.7% - 28.4%  respectively.  In treatment naive patients, who were given ipi at 10mg/kg, 4-year survival rates were 37.7% - 49.5%.

CONCLUSIONS:  These results demonstrate durable survival in a significant proportion of patients with metastatic melanoma who received ipi.

MY TAKE:  Not bad for melanoma world, in which average survival for an untreated patient with metastatic melanoma is roughly 6 months.  Ipi is a legitimate treatment option for many patients and these data clearly show that treatment naive patients respond much better, as do those with a dosing level of 10mg/kg.

Keep on hanging on - c

I'm an I.N.D.E.P.E.N.D.E.N.T. Sh*# Hustler.....

Chasing dreams...since I was 14
Fat cat, pharma...labels out here!
Nah, they can't tell me noth'n.
I give it to the people,
Spread it across the country.

Can we go back? This is the moment!  Tonight is the night, we'll fight til it's over.
So, we put our hands up, like the ceiling can't hold us.  Like the ceiling can't hold us!!!

Now, can I get a 'Kick it'?  Thank you!!!
Yeah, I'm so damn grateful.  I grew up, really wanted to make a difference.
That's what you get when you see the world suffer.
Melanoma can't stop me.
I go hard like I got an 808 in my heart beat, and I'm living to the beat
Like you gave a little speed to a great white shark, on Shark Week!  RAW!

Time to take off.  Don't have time for insurance asses!!  Doctors that won't tell what the fact is!
I'm gone!
My validation comes from giving it back to the people.
I sing my song.....and it goes like.....
Raise those hands, this is our party
We came here to live life like nobody was watching
I got my peeps right behind me....and if I fall...
They got me.
Learn from that failure, gain humility....then we keep MARCHING.  
Let's go!


Thanks to all my peeps who give me the strength to keep marching, pushing, searching, writing. And to Macklemore....for my latest anthem.

Macklemore, Can't Hold Us

On the home front....tongue feels like it has been on the wrong end of a cheese grater...again...since middle of last week.  Thought it was getting a little better, then a host of new lesions.  What the tub???  Spring is beautiful.  Just had my tri-monthly fight with the hired collecting gun of Erlanger's billing arm.  ASSHOLES!!!!!  Pay your bill in full in a timely fashion and they STILL HARASS you!!!  Fabulous. I've doubled the miles I'm running each week.  But, I have only one wish....for each of YOU - to LIVE.....LARGE.....like nobody was watching!!!!! - c

New treatment for melanoma!!!! - ADC's - Antibody-Drug Conjugate

New scoop!!!! New trial!!!!   So...what the heck is an ADC????

ADC and the NCT01522664, Phase I trial, Genentech/Roche, ADC, Antibody Drug Conjugate DEDN6526A

An ADC (antibody drug conjugate) is like a Trojan Horse!!!  It takes a bad ass cytotoxin, like auristatin (that's the one being used here), an anti-mitotic agent that derives its action by preventing tubulin polymerization and therefore stops cell division, attaches it via a special molecule to a monoclonal antibody that targets antigens preferentially expressed on the surface of the targeted cancer cells..in this case, Endothelin B.  This method allows patients to survive being treated with really toxic agents without suffering the terrible side effects that would certainly ensue should those cytotoxins be injected directly.  By taking them under cover, only the bad cells we want to target are damaged.

ADC's have been in the works since the 80's. Over that time laboratory researchers have found many more possible antibodies to use (and studied which tumors express them the most) and a variety of gradually improving techniques to "link" the chemotherapeutic agent to the antibody. Improved "linkers" seem to have made it easier to use a variety of antibodies as well as cytotoxic agents while keeping the whole little trifecta intact until it reaches its destination.  Patent information seems to indicate that researchers feel they may even be able to target infectious organisms in the future.  Two ADC's have been marketed for lymphoma and leukemia.  And, just a couple of weeks ago, Celldex got FDA approval for CDX-011 (glembatumumab vedotin) as a treatment for Her-2 breast cancer.  Interestingly, initially, this drug which uses "auristatin conjugated to a monoclonal antibody that recognizes GPNMB, expressed at higher levels in melanoma and breast tumors"  was tested in patients with melanoma as well as breast cancer.  Sievers and Senter, in a Seattle Genentech report state, "In a phase I/II trial in patients with unresectable late-stage melanoma, CDX-011 showed overall response rates ranging from 14% to 19% depending on dosing frequency and GPNMB expression levels."  However, at this point, it seems that this particular ADC is no longer being utilized in melanoma trials.

Back to the ADC at hand...Genentech's GR-7636:  This drug targets Endothelin receptor ETB, which is apparently expressed on most melanoma tumors (as well as skin cells in general....and is even in the pathway for their embryonic development....which explains why one of the side effects can be skin irritation and rashes).  So much so...that at first folks tried the drug bosentan, a dual endothelin A/B receptor antagonist which is similar to anti-PD1 in that it uses an antibody to modify a specific cell receptor, but UNLIKE anti-PD1, the receptor is on the melanoma cell itself, and the hope was that by antagonizing it [blocking it] the cell would die....while anti-PD1 hopes to activate white cells and bring the immune system to attack the tumor cell.  Anyhow, they tried bosentan alone and combined with dacarbazine but had disappointing results.

One other note on Endothelin B and its expression in melanoma cells:  In the Asundi paper:  They assayed the amount of cell expression of the receptor and found it to have a range of expression from 1500 to 33000 per cell line. In their mouse model, they showed efficacy of their ADC for both the low and high end of cell expression.

So.....it seems that researchers have found a very melanoma specific, cell surface receptor, which provides a target using antibodies bonded to a highly potent cell toxin which is rapidly taken in from the cell surface and converted to the active agent inside the cell.  Theoretically, this will allow targeted delivery of extremely cytotoxic agents and in the mouse model produced rapid (i.e. one week) death of melanoma cells with no recurrence for three months.  Luckily, a dear one of mine, is embarking on this rattie adventure at Sarah Cannon in Nashville.  There, though they are only reporting on 15-20 patients currently enrolled, they say that they have determined the most effective dose and schedule, side effects have been minimal, responses are clear (or not) by 6 weeks, and are attaining about a 30% response rate. Due to the explanation above, prior ipi or anti-PD1 is NOT an obstacle since this regimen works in an entirely different fashion.  Recruitment is apparently 1 patient per every 3 week cycle, per trial site.

Wishing you the best in your rattie adventure, J.  Hang tough, all of you. - c


Bibliography:

An antibody-drug conjugate targeting the endothelin B receptor for the treatment of melanoma.
Asundi, et al.  Clinical Cancer Research. 2011 Mar 1;17(5):965-75  Genentech, Inc, San Fran, CA

Antibody-drug conjugates in cancer therapy.  Sievers and Senter. Anne. Rev. Med. 2013. 64:15-29.  First published October 3, 2012.  Seattle Genetics, Bothell, Washington.

Antibody-drug conjugates.  Zolot, Basu, Million.  Nature Reviews. April 2013, Vol 12.

Maturing antibody-drug conjugate pipeline hits 30.  Mullard. Nature Reviews. May 2013, Vol 12.

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.

TRANSLATION:
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
 

Female baldness. Cancer Treatment. Rapunzel.

Long luxurious locks are firmly associated with beauty and strength, no matter if you're talking Samson or top super models.  For myself, I am pretty relaxed about my hair, having had it in pixie cuts at least 4 different times in my life, as well as lengths past my shoulders, bobs, shags, and just about everything in between.  As Ruthie puts it, "Anytime a crisis happens, you chop off your hair."  She's right.  A close look at this blog shows that hair past my shoulders was quickly lopped into a bob on my learning that I was about to have a halo placed for brain radiation followed within days by lung surgery that was expected to land me on a vent in the intensive care unit.  I've worked in that scene and knew I didn't need any extra hair to add to that adventure!!!  But, for such a cavalier attitude, even I, dreaded the thought of being bald, and really, really didn't like the prospect one bit when faced with treatment options that might have rendered me so.  It turned out, that thus far, I haven't had to use them...but still.  I know how much I didn't want to be bald.

So, why is that?  Why, as a society do we consider Demi Moore's baldness for G.I. Jane a publicity stunt?  But, when Matthew McConaughey loses 30 pounds, or DeNiro gains 60 for a role...it is for art?  Clearly, appearance in men and women are judged very differently.  Men with grey hair (think the beautifully aging Clooney and Sean Connery) are considered incredibly handsome.  Women...not so much. Baldness in men will not only make you swoon (Bruce Willis, Jason Statham, Vin Diesel), but they kick ass!!!

So....ultimately, we women do this to ourselves.  While they are not touted for their particular beauty in those moments.....no human was ever lovelier than Natalie Portman in V for Vendetta, Sinead O'Conner back in the day, (gotta say...the girl's let herself go a bit, lately) or Ingrid Bergman in  For Whom the Bell Tolls.  As beautiful Halle Berry said, "Short hair is an accessory that I get to wear - like a handbag or shoes."  So, let's go with that!  To shave your head or chop your locks for a movie role or a fashion statement is NOTHING, compared to the strength of character, the spirit of determination, the absolute courage in the face of incredible odds that a cancer patient accepts, knowing that a treatment might save your life...or end it...AND leave you bald.

So....  I raise a glass to all the bald and beautiful, courageous warriors among us.  After all...Rapunzel would have been a lot smarter if she had chopped her locks, made her own ladder OUT of the tower, and found the life and prince SHE wanted....instead of settling for the one that found her.

Bald is more than beautiful, baby!!!! - c

21...how can it be????

But, how beautiful she is.  Happy birthday, Rosie Roo.  I LOVE YOU!!!!!! - mommy

Melanoma May and Cherry Trees after 5 years NED = cured (NOT) 10 melanoma years later

 

 

My three cherry trees that Brent planted in celebration when I was almost 5 years out from my first round with a positive axillary node from melanoma, and theoretically CURED!!!!!...were really beautiful this year, ten years and many melanoma episodes later.  May is Melanoma Awareness month.  A designation that I meet with mixed feelings.  However, if this proclamation can curtail behaviors that may contribute to the development of melanoma, or encourage those with suspicious skin lesions...especially with a history of melanoma...to have them checked by a dermatologist, then it is more than worth it.  Melanoma doesn't play by the rules. Sadly, 5 years NED does NOT equal cured in melanoma world.  Stay vigilant.  Stay aware.  Stay tough.  And...enjoy the blossoms along the way.  Love - c

Nah nah...nah na nah na!!

What the tub???!! 18 wheeler pushes me off the road (completely), in bumper to bumper traffic, on my way home today. Driver (????) finally notices I'm driving on the rumble strip as I and the cars in front and behind me are honking madly, waves sweetly and moves back over, and I am allowed to get back on the actual roadway. Thank you, dear trained professional driver of incredibly large truck. I'm just little 'ol me, untrained as I am. You, of course, know how to drive best...being a professional and all that.  Freak!!!!

And then, yesterday....old dude in bright yellow Boxster, thinks he can beat me and my Juke up the front of the mountain! What has happened to the world?? Never gonna happen!

Be careful out there! Some folks are cray cray!!

Nah nah, nah na nah na! Hey hey hey oh e hey! Drive safe! - c