Markers for response to immunotherapy: Increased eosinophils = good. Increased Myeloid Suppressor cells = not so good.

Myeloid Cells and related chronic inflammatory factors as novel predictive markers in melanoma treatment with ipilimumab.  Gebhardt, Sevko, Jiang, et al.  Clin Cancer Res. 2015 Aug 19.

Ipi improves survival of patients with metastatic melanoma.  Since only about 20% of patients experience long-term benefit, reliable markers are needed to predict response.  Analysis of blood of 59 Stage IV melanoma patients was analyzed before treatments and at different times during treatment.  An early increase in eosinophil count during treatment with ipi was associated with an improved clinical response. In contrast, elevated numbers of monocytic myeloid-derived suppressor cells (moMDSCs), neutrophils, and monocytes were found in non-responders (n=36) as compared to levels in responding patients (n=23).  Non-responders also produced more nitric oxide and granulocytic MDSCs expressed higher levels of PD-L1 ... suggesting their enhanced immunosuppressive capacity.  Upon the first ipi infusion, non-responders displayed high serum concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.

So....folks with increased eosinophils do better.  Folks with increased numbers of myeloid-derived suppressor cells, neutrophils, and monocytes do not.  Here is more data to support the same findings:

Lab values that may predict response to Ipi

Eosinophilia and a positive response to nivo and pembro

In this link Weber talks ipi and combo's, several immunotherapy combo's are discussed...but the relevant part addresses the blood work from the folks taking nivo in my study:
 

Looking at pretreatment parameters in the periphery and the tumor-
Only baseline MDSC, myeloid derived suppressor cells, proved to be significant.
These are CD14, HLA-DR low, CD11 B+ cells, classic myeloid derived suppressor cells which express high levels of PDL1 and other check point proteins.
Neutrophil derived MDSC cells were not related.
The more myeloid suppressor cells you have, the worse the patient did both in response rate and survival. 
Weber hopes to soon have results of the levels of MDSC from within the tumors of these patients and see how that level related to outcomes.
You can block MDSC by incubating it with PD1 antibody as well as other check point proteins, so he is writing a grant proposal currently to test a combo of nivo with MDSC depletion.
Measurements of the T-regs in the periphery - Levels decreased in responders, in non-responders it went up. For this reason, also thinks that nivo with T-reg depletion is worth investigation.


Here, in a synopsis of articles about the positive effects of combining immunotherapy and radiation, Radiation for melanoma, better when combined with immunotheapy!, once again....patients do better when MDSCs are few and far between:  Concomitant with tumor regression from radiation, they noted that radiation and anti-PD-L1 worked together to reduce the local accumulation of tumor-inflitrating myeloid-derived suppressor cells (MDSCs)... {Note:  Remember, these are the bad guys that block your T cells.  In my study, the folks with high levels of MDSCs did least well, while those with the lowest levels did better.  That's why, some researchers, like Weber, are talking about depleting these cells in patients FIRST...then administering anti-PD1 or other immunotherapies!!}  So...the data acquired in this study demonstrated evidence of the interaction between radiation and T cells....and a basis for the rational design of combination therapy with immune modulators and radiotherapy.

Really thinking the idea about depleting MDSCs at the start may really be the way to go here!!!  Best - c 

It's not ALL melanoma up in here!!

Sometimes it's the cutest house for the cutest, most hard working girl!!!  Yep!  Roo, got her masters in education while completing a year with a Project Inspire Program teaching at a high need, inner city high school, and got a job teaching Algebra 2, Pre-Cal, and Calculus at a local school this year!  Meanwhile, she saved her pennies.  Got a house.  Fixed it up.  Moved in a couple of weeks ago!  WOW!

Come in and have a seat!

Plan a lesson!

Cook a meal....with curtains made from material courtesy Ruthie, that was pillow covers in various dorms and apartments and is now curtains 'a la a Parisian cafe!

Art from B, and table snagged by a girl with a discerning eye from local biz going out of business, refurbished by the amazing guys at Grain Surgeons furniture repair!

Can you say chairs for Ten Bucks each at the Zillion Mile yard sale?  A little sanding, a little spray paint.....

A cute cover for the rough spots!

Art by Roo.  Gifted quilt.  Curtains left behind by prior owners, cut to size, cute buttons applied, and old throw pillow given a new lease on life!

Bath room tub and tile re-glazed to beauty!  Shower curtain and valance made by me...yes indeed!

Wide Open Spaces
Sorry, Roo.  But, you knew it was coming!!! So very proud of my girl.  So very lucky to get to share this special time with you.  Much love, my dear.  - mommy

Jimmy Carter, Melanoma, and me...

Given that those of you who have followed this blog for more than ten minutes would certainly agree that I am a weird adult, you will not be surprised to learn that I was a strange child.  Born in 1964, I talked early and a lot (so I'm told).  I had a simultaneous aversion and attraction to things that were "suzzy"! (No one says I spoke with good pronunciation!) So much so, that my dear Granny made me a decoupage picture of kittens that I still have.  I could memorize poems and songs easily.  I wanted to please.  And I remember perfectly clearly three events that touched my heart and made me see just how big the world really was from a very small town in south Alabama.

I have to believe that my desire to help the children pictured in a National Geographic magazine showing the devastating effects of famine in Africa led me to the career path of pediatric nursing of which I have been a part since 1984.  I spent so much time looking sadly at the pictures that my family finally hid the magazine.

In 1972, when I was in the 5th grade, I remember explaining to my classmates the story of Watergate.  It was my first glimpse into the pompous hubris of the powerful and the absolute stupidity of being taped or filmed, knowing that there is a record that can eventually be replayed - clearly showing the truth - yet denying that very truth publicly.  I still cannot believe the great numbers of folks who have not learned this lesson as we watch such ridiculousness play out daily.

But, in 1978, through the efforts of the Israeli prime minister Menachem Begin, Egyptian president Anwar Sadat, and American President Jimmy Carter, a peace agreement between Egypt and Israel was achieved.  I watched the talks and interviews with rapt attention on the evening news shows.  THIS was what men could do when their hearts were in the right place, political opinion was deemed less important than what was best for real people, and power was used constructively!  I have adored Jimmy Carter ever since.  His lack of willingness to "play" the system may have made him something less than an impressive president.  But his intelligence, his work ethic, his sense of right and justice and willingness to speak out....have made him an amazing human who has made an incredible difference in this world.  Post presidency he has continued to be a leader in pushing for world peace with diplomatic work in Korea, Israel and Palestine with the achievement of the Geneva Accord, Africa, and Vietnam.  The Carter Center, a non-profit he founded in 1982 with his wife and Emory University, has made an incredible difference in the lives of people across the globe.  His reputation allowed him to develop and institute the process of election observation to help ensure free and fair elections in countries world wide.  The Center supports those working to safeguard human rights.  The positive steps Carter's Center has made in the health of millions is unbelievable.  The near eradication of the Guinea Worm, through simple education and water filtration, is nothing less than heroic. (Here's a link to show just how yucky Guinea Worm infestation can be:  Dracunculiasis - Guinea Worm Infestation ) In 1986 there were more than 3.5 million cases annually across 20 countries in Asia and Africa.  In 2013, there were only 148 cases in 4 countries. Here is a clip of Carter being interviewed by John Stewart about that very thing, noting that by 2015 Guinea worm cases were down to 126:  Jimmy Carter on The Daily Show in 2015   I love that some of his greatest successes were born out of the simplest, common sense techniques:  Jimmy Carter talks Guinea Worm filters and latrine building to stop trachoma

What a man.  So incredibly brilliant, funny, determined, and humble.  And now....he has Stage IV melanoma.  Apparently since his melanoma diagnosis in early August with a liver biopsy and an MRI showing additional brain mets, he has started anti-PD1 (Keytruda) and is to have SRS to brain mets very soon at Emory in Atlanta.  Good moves, sir!  If fighting melanoma is something you must do, after all the other things you have done...this is exactly how I would go about it.  Anti-PD1 has some of the best results going (topped only by the ipi/nivo combo...but that brings increased side effects as well) and when dealing with brain mets, combining immunotherapy WITH radiation gives better results than either therapy alone.  In fact, in the case of ipi, "Patients treated with SRS during or before ipi had better overall survival and less regional recurrence." Here's a link to data regarding the combo:  Radiation for melanoma: better when combined with immunotherapy

You are in my heart, President Carter.  You have led the way for so many.  Perhaps, some of us melanoma ratties have led the way for you.  I wish you well. - c

Immune related side effects from immunotherapy can and SHOULD be treated!!!!

Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center.  Horvat, Adel, Dang, et al.  J Clin Oncol.  2015 Aug 17.

Ipilimumab is a standard treatment for metastatic melanoma, but immune-related adverse events (irAEs) are common and can be severe. We reviewed our large, contemporary experience with ipilimumab treatment outside of clinical trials to determine the frequency of use of systemic corticosteroid or anti-tumor necrosis factor α (anti-TNFα) therapy and the effect of these therapies on overall survival (OS) and time to treatment failure (TTF).

We reviewed retrospectively the medical records of patients with melanoma who had received treatment between April 2011 and July 2013 with ipilimumab at the standard dose of 3 mg/kg. We collected data on patient demographics, previous and subsequent treatments, number of ipilimumab doses, irAEs and how they were treated, and overall survival.

Of the 298 patients, 254 (85%) experienced an irAE of any grade. Fifty-six patients (19%) discontinued therapy because of an irAE, most commonly diarrhea. Overall, 103 patients (35%) required systemic corticosteroid treatment for an irAE; 29 (10%) also required anti-TNFα therapy. Defining TTF as either starting a new treatment or death, estimated median TTF was 5.7 months. Twelve percent of patients experienced long-term disease control without receiving additional antimelanoma therapy. OS and TTF were not affected by the occurrence of irAEs or the need for systemic corticosteroids.

IrAEs are common in patients treated with ipilimumab. In our experience, approximately one-third of ipilimumab-treated patients required systemic corticosteroids, and almost one-third of those required further immune suppression with anti-TNFα therapy. Practitioners and patients should be prepared to treat irAEs and should understand that such treatment does not affect OS or TTF.

Pancreatitis Secondary to Anti-Programmed Death Receptor 1 Immunotherapy Diagnosed by FDG PET/CT.  Alabed, Aghayev, Van den Abbeele.  Clin Nucl Med. 2015 Aug 18. 

A 57-year-old man with metastatic melanoma developed colitis secondary to ipilimumab, a known immune-related adverse event (irAE). The patient then received pembrolizumab immunotherapy, an anti-programmed-death-receptor-1 (PD-1) antibody. Restaging FDG PET/CT study following 3 cycles of therapy demonstrated diffuse increased FDG uptake throughout the body of the pancreas associated with fat stranding in the peripancreatic region, suggestive of pembrolizumab-induced pancreatitis. Although the patient was clinically asymptomatic, diagnosis was biochemically confirmed with elevated amylase and lipase levels. In the era of immunotherapy, it will be critical to recognize irAEs early to allow prompt initiation of appropriate therapy and reduce the risk of long-term sequelae.

I posted this in 2014:  Melanoma patients teach us more about complications with ipi

It is becoming more and more clear that the old "bug-a-boo" of, "Oh, you're on anti-PD1 (or ipi)!  You can't treat side effects with prednisone or any other immune suppressing medication!!!  If you do, the therapy won't work on your melanoma!" IS WRONG!!!!!!!!!  Rather, if immune side effects are noted as soon as possible and TREATED, it is much more likely that the melanoma patient can continue their needed treatment (perhaps with a drug holiday for a brief time), still receive benefit from that treatment, and diminish the likelihood of long-term problems from those side effects!

Be vigilant my friends.  And, be sure that you are going to a doc who knows how to recognize and TREAT any side effects that may develop.  Yours - c

This one's for you, Artie! Electro/chemo to zap tumors!

ELECTROCHEMOTHERAPY TO METASTATIC SPINAL MELANOMA: A NOVEL TREATMENT OF SPINAL METASTASIS?   Gasbarrini, Campos, Campanacci, et. Spine. 2015 Aug.

Electrochemotherapy is a new antitumor treatment that combines systemic bleomycin with electric pulses delivered locally at the tumor site. These electric pulses permeabilize cell membranes in the tissue, allow bleomycin delivery diffusion inside the cells, and increase bleomycin cytotoxicity. Previous clinical studies have demonstrated the effectiveness of Electrochemotherapy in the treatment of several primary and metastatic solid tumors. Treatment planning for electrode positioning and electrical pulse parameters was prepared for four needle electrodes. Mini-open surgery with a left L5 laminectomy was performed to introduce the eletrodes. The assessed follow-up period was 48 months after the Electrochemotherapy procedure. Neither serious Electrochemotherapy-related adverse events, nor bleomycin toxicity were reported. Overall improvement in pain, ODI [level of disability] and KPS [performance] outcomes was better. Our case represents, to our knowledge, the first one to test the potential role of Electrochemotherapy as treatment of spinal metastasis. Electrochemotherapy allowed a successful treatment of metastatic spinal melanoma. However, we believe that there is a strong scientific rationale to support the potential utility of Electrochemotherapy as a novel treatment of spinal metastasis, regardless of the histological types. Super new.  No impact on or survival data included.  Don't know where it is offered in the US. Melanoma doesn't usually respond to "normal" chemo.  But in this treatment methodology...zapping the tumor with electrodes first seems to make them more responsive to the chemotherapy....that was then administered systemically. (Wonder why they didn't try a local injection???) Reminds me a bit of the ADC therapy J tried where nasty ass chemo was linked to a monoclonal antibody that (in theory) would be drawn into the tumor cells only.  Once there, the chemo would be unleashed. Here's a post on that one:  ADC's - Antibody Drug Conjugate Unfortunately, while ADC therapy held tumors in check for some...there was pretty substantial chemo leakage that led to typical chemo side effects:  hair loss, fatigue, loss of appetite, neuropathy, etc.  So...don't know if you could even access this treatment, Artie....but it is one of the ways folks are trying to make old time chemo work for melanoma patients.  Warm wishes to you all - C

Positive response to Helper Peptide Vaccines for melanoma

Long-term Outcomes of Helper Peptide Vaccination for Metastatic Melanoma.  Hu, Kim, Blackwell, Slingluff.  Ann Surg. Sep 2015

 

The objective of this study was to compare the long-term outcome of patients with metastatic melanoma vaccinated with 6MHP to that of a group of unvaccinated historical controls. A multipeptide vaccine (6MHP), designed to induce helper T cells against melanocytic and cancer-testis antigens, has been shown to induce specific Th1-dominant CD4+ T cell responses. The 6MHP vaccine was administered to patients with metastatic melanoma. Circulating CD4+ T cell responses were measured by proliferation or direct IFN-gamma ELIspot assay. Overall survival of vaccinated patients was compared to a group of clinically comparable historical controls using multivariable Cox regression analysis and Kaplan-Meier survival analysis, taking into account age, metastatic site, and resection status. Across 40 vaccinated patients and 87 controls, resection status and vaccination were associated with improved overall survival. Forty pairs of vaccinated patients and controls were matched by metastatic site, resection status, and age within 10 years. Median survival was significantly longer for vaccinated patients (5.4 vs 1.3 years). Among the vaccinated patients, the development of a specific immune response after vaccination was associated with improved survival. Helper peptide vaccination is associated with improved overall survival among patients with metastatic melanoma. These data support a randomized prospective trial of the 6MHP vaccine. I was given 6 peptide vaccines IM every two weeks with every infusion of nivo I received for the first 6 months of my trial.  It was determined that they did no good and administration of them was ceased in patients who followed my cohort.  Link to the explanation of their use:  My anti-pd1/vaccine trial results 2012  However, in 2013, there was this out of MD Anderson:  Peptide Vaccines do not trigger effective immune response  BUT!  My vaccine was quite different from this one!!!  I still hold out hope that vaccines will be the answer to at least some, if not all, of the curing melanoma equation!!! Best to you all - c

Being female with low LDH, no ulceration in primary, and BRAF V600E positive = increased rates of survival with BRAFi for melanoma patients?!!!

Clinicicopathologic features associated with efficacy and long-term survival in metastatic melanoma patients treated with BRAF or combined BRAF and MEK inhibitors.  Menzies, Wilmott, Drummond, et al.  Cancer.  Jul 28, 2015.

For 142 consecutive immunotherapy - and MAPK inhibitor-naive patients with BRAF-mutant metastatic melanoma who were treated during clinical trials with BRAFi (n=111) or the combo of dabrafenib and trametinib (n=31), clinicopathologic factors were correlated with the response to MAPK inhibitors and survival.

Median f/u = 15.7 months.  The 2, 3, and 4 year overall survival (OS) rates were 43%, 24% and 24% respectively.  Statistical analysis demonstrated that the only clinicopathologic factors associated with longer Progression Free Survival (PFS) and OS were being female and a normal pretreatment serum lactate dehydrogenase (LDH) level.  BRAF V600E genotype and an absence of primary melanoma ulceration were also independently associated with longer PFS but not with OS.  The median OS was 23.5 months for patients with normal LDH levels and 7.3 months for those with elevated LDH levels.  Complete responders had the best survival, but disease progression still occurred in 2 of 7 patients.

We certainly need to figure out what treatment works for whom.  I think it is important to note that these patients were all treatment naive...apparently.  For whatever that is worth.  This provides the first real confirmation of the importance of a low LDH to outcome that I have seen.  It also provides one more bad mark for ulceration of primary lesion, as that has long been noted to be related to a poorer prognosis.  

Hang in there, peeps! - c