Wednesday, May 23, 2018

ipi/nivo efficacy in melanoma brain mets, CD8+ T cell actions, and (surprise, surprise!!!) CONCURRENT radiation and immunotherapy is even better in brain mets


I've only said most of this post a zillion times.  Brain mets suck great big hairy green wizard balls!!! We know immunotherapy works in the brain and body.  AND...we KNOW that immunotherapy combined with radiation works even better for brain mets.  But...we begin again...

We'll start with a bit of relatively new information at the cellular level:

Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking. Taggart, Andreou, Scott, et al.  Proc Natl Acad Sci U S A. 2018 Jan 31.

Inhibition of immune checkpoints programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on T cells results in durable antitumor activity in melanoma patients. Despite high frequency of melanoma brain metastases (BrM) and associated poor prognosis, the activity and mechanisms of immune checkpoint inhibitors (ICI) in metastatic tumors that develop within the "immune specialized" brain microenvironment, remain elusive. We established a melanoma tumor transplantation model with intracranial plus extracranial (subcutaneous) tumor, mimicking the clinically observed coexistence of metastases inside and outside the brain. Strikingly, intracranial ICI efficacy was observed only when extracranial tumor was present. Extracranial tumor was also required for ICI-induced increase in CD8+ T cells, macrophages, and microglia in brain tumors, and for up-regulation of immune-regulatory genes. Combined PD-1/CTLA-4 blockade had a superior intracranial efficacy over the two monotherapies. Cell depletion studies revealed that NK cells and CD8+T cells were required for intracranial anti-PD-1/anti-CTLA-4 efficacy. Rather than enhancing CD8+ T cell activation and expansion within intracranial tumors, PD-1/CTLA-4 blockade dramatically (∼14-fold) increased the trafficking of CD8+ T cells to the brain. This was mainly through the peripheral expansion of homing-competent effector CD8+ T cells and potentially further enhanced through up-regulation of T cell entry receptors intercellular adhesion molecule 1 and vascular adhesion molecule 1 on tumor vasculature. Our study indicates that extracranial activation/release of CD8+ T cells from PD-1/CTLA-4 inhibition and potentiation of their recruitment to the brain are paramount to the intracranial anti-PD-1/anti-CTLA-4 activity, suggesting augmentation of these processes as an immune therapy-enhancing strategy in metastatic brain cancer.

OK....so that sounds important and impressive.  Now, there's this, which probably explains a bit of the above:

CD103+ tumor-resident CD8+ T cells are associated with improved survival in immunotherapy naive melanoma patients and expand significantly during anti-PD1 treatment. Edwards, Wilmott, Madore, et al.Clin Cancer Res. 2018 Mar 29.
Therapeutic blockade of immune checkpoints has revolutionized cancer treatment. Durable responses however, occur in less than half of those treated and efforts to improve treatment efficacy are confounded by a lack of understanding of the characteristics of the cells that initiate anti-tumor immune response.  

We performed multi-parameter flow cytometry and quantitative multiplex immunofluorescence staining on tumor specimens from immunotherapy-naïve melanoma patients and longitudinal biopsy specimen obtained from patients undergoing anti-PD-1 therapy.
Increased numbers of CD69+CD103+ tumor-resident CD8+ T cells was associated with improved melanoma-specific survival in immunotherapy-naive melanoma patients. Local IL-15 expression levels strongly correlated with these tumor-resident T cell numbers. The expression of several immune checkpoints including PD-1 and LAG3 was highly enriched in this subset and these cells significantly expanded early during anti-PD-1 immunotherapy. 

Conclusions: Tumor-resident CD8+ T cell numbers are more prognostic than total CD8+ T cells in metastatic melanoma. In addition, they are likely to initiate response to anti-PD-1 and anti-LAG-3 treatments. We propose that the immune profile of these cells prior to treatment could inform strategies for immune checkpoint blockade.

Ok.  That is good to know!  Now...how to we make that happen?????

And of course...no melanoma brain met post is complete unless I'm yelling!!!!  So here are a zillion posts about the benefit of immunotherapy COMBINED with radiation for brain mets:

CONCURRENT radiation and immunotherapy for brain mets is BEST!!!! (yes, AGAIN!!!)

And yes...there is this shocking finding!!!  The ipi/nivo combo is better in treating melanoma in the brain than nivo alone!!!  AGAIN!!!  (Just like in the body....sigh....)

Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Long, Atknson, Lo, et al.  Lancet Oncol. 2018 Mar 27.

Nivolumab monotherapy and combination nivolumab plus ipilimumab increase proportions of patients achieving a response and survival versus ipilimumab in patients with metastatic melanoma; however, efficacy in active brain metastases is unknown. We aimed to establish the efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with active melanoma brain metastases.
This multicentre open-label randomised phase 2 trial was done at four sites in Australia, in three cohorts of immunotherapy-naive patients aged 18 years or older with melanoma brain metastases. Patients with asymptomatic brain metastases with no previous local brain therapy were randomly assigned using the biased coin minimisation method, stratified by site, in a 30:24 ratio (after a safety run-in of six patients) to cohort A (nivolumab plus ipilimumab) or cohort B (nivolumab). Patients with brain metastases in whom local therapy had failed, or who had neurological symptoms, or leptomeningeal disease were enrolled in non-randomised cohort C (nivolumab). Patients in cohort A received intravenous nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks; patients in cohort B or cohort C received intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was intracranial response from week 12. Primary and safety analyses were done on an intention-to-treat basis in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02374242, and is ongoing for the final survival analysis.

Between Nov 4, 2014, and April 21, 2017, 79 patients were enrolled; 36 in cohort A, 27 in cohort B, and 16 in cohort C. One patient in cohort A and two in cohort B were found to be ineligible and excluded from the study before receiving the study drug. At the data cutoff (Aug 28, 2017), with a median follow up of 17 months (IQR 8-25), intracranial responses were achieved by 16 (46%) of 35 patients in cohort A, five (20%; 7-41) of 25 in cohort B, and one (6%; 0-30) of 16 in cohort C. Intracranial complete responses occurred in six (17%) patients in cohort A, three (12%) in cohort B, and none in cohort C. Treatment-related adverse events occurred in 34 (97%) of 35 patients in cohort A, 17 (68%) of 25 in cohort B, and eight (50%) of 16 in cohort C. Grade 3 or 4 treatment-related adverse events occurred in 19 (54%) patients in cohort A, four (16%) in cohort B, and two (13%) in cohort C. No treatment-related deaths occurred.

Nivolumab combined with ipilimumab and nivolumab monotherapy are active in melanoma brain metastases. A high proportion of patients achieved an intracranial response with the combination. Thus, nivolumab combined with ipilimumab should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases.

Why in the world the poor folks in Cohort C had to get the shaft TWICE, I don't know!!  Once in being the poor peeps who had already failed a therapy and/or had symptomatic disease and secondly by being given the less effect treatment....DAMN!  Anyhow, as usual, I digress...  So folks with untreated brain mets with no symptoms were put into two groups.  Group A got ipi/nivo and 46% gained a response.  Group B got nivo alone and attained a 20% response rate.  And as noted, the folks with symptoms and/or had already failed one treatment for their brain mets were put into Group C and given nivo only, where they had only 1 response in their n=16.  So...small numbers here...and to me this serves only as reinforcement for what we already know: YES!!!! Immunotherapy works in the brain!!!!  (BUT....even better WITH SRS or gamma knife radiation therapy....circle back to above!!!!)

For what it's worth... - c

Saturday, May 19, 2018

Sew Chaotically! - A coral Basic InstincT


My #basicinstinctshirt by Sasha went together perfectly and works well with any bottom!!!  I decided Roo needed one too.  When I found this super luscious and silky jersey from Mood, I know it would be just the thing!  And it could not have gone better with her wardrobe re-boot....

You may remember the wardrobe review and repair post!
....which included the purple ruched top, along with the Purple Work-out Top and the coral Faux Wrap Dress!
So now...The Sasha Basic InstincT!!!
I can't tell you how nice this pattern is!!!  It is perfectly drafted and so easy to dress up or down!
Again, Roo was a sport, letting me snag a photo before we ran off to our work out!  I know she'll get lots of use out of this top at work and play!
Seriously, y'all!!  You gotta check out Sasha!  Here's a link to her blog:  Secondo Piano  She makes the coolest things and includes lots of inspo on how to hack her very own pattern - Basic InstincT ( a t-shirt pattern).  And crazy woman!  As if that's not enough, the pattern is FREE!!!!!
Thanks, Sasha!  Sew Chaotically!!! - les

Thursday, May 17, 2018

Whatever it takes!!!


Melanoma steals so much from so many.  It frightens all of us if we think upon it too long.  It petrifies those newly diagnosed ~ almost beyond bearing.  Still, it has allowed me to meet, and know, and love, REAL heroes whose outlook on life, while forever changed, is nothing short of amazing.  They light my path.  They bring me smiles.  They inspire my efforts.  They give me strength.  I want to be just like them when I grow up!!!  So, for ALL of you there is this ~

(With much credit and appreciation to - Imagine Dragons!!!  Listen to the link, words below.)

Whatever It Takes - Imagine Dragons

Falling too fast to prepare for this
Tripping in the world could be dangerous
Everybody circling is vulturous
Negative, nepotist
Everybody waiting for the fall of man
Everybody praying for the end of times
Everybody hoping they could be the one
I was born to run, I was born for this.

Whip, whip
Run me like a race horse
Pull me like a ripcord
Break me down and build me up
I wanna be the slip, slip
Word upon your lip, lip
Letter that you rip, rip
Break me down and build me up

Whatever it takes
'Cause I love the adrenaline in my veins
I do whatever it takes
'Cause I love how it feels when I break the chains
Whatever it takes
You take me to the top, I'm ready for
Whatever it takes
'Cause I love the adrenaline in my veins
I do what it takes.

Always had a fear of being typical
Looking at my body feeling miserable
Always hanging onto the visual
I wanna be invisible

Looking at my years like a martyrdom
Everybody needs to be a part of 'em
Never be enough, I'm the prodigal son
I was born to run, I was born for this.

Hypocritical, egotistical
Don't wanna be the parenthetical, hypothetical
Working hard on something that I'm proud of, out of the box
An epoxy to the world and the vision we've lost
I'm an apostrophe
I'm just a symbol to remind you that there's more to see
I'm just a product of the system; a catastrophe
And yet a masterpiece, and yet I'm half-diseased
And when I am deceased
At least I'll go down to the grave and die happily
And leave the body and the soul to be a part of thee ~

I do what it takes.

Whatever it takes
'Cause I love the adrenaline in my veins
I do whatever it takes
'Cause I love how it feels when I break the chains
Whatever it takes
You take me to the top, I'm ready for
Whatever it takes
'Cause I love the adrenaline in my veins
I do what it takes.

And so we melanoma peeps do ~ whatever it takes.  At times, merely whatever it takes to make it through an hour, or day.  But, bit by bit, we grow stronger than melanoma.  No matter what that bitch tries to dish out.  Despite forever half diseased, we are a masterpiece!   

With sincere appreciation and remembrance - Artie, Patti, Josh, Juan, Ms. Ituah (and daughter), Bob, Santos, Dfeng, Jamie, Paul, and Rob's Adriana - you are forever part of my heart.

Great thanks to my dear J and F, Jeanne, Eric, and Ed.  You guys rock and are part of the foundation on which I stand. Tammy B, Danita, Ashia, Anita - you stand by me, watch me like mother hens, and put up with NONE of my BS!  It is a blessing.  Roo, your spirit and determination are contagious.  I would not be running or doing those push-ups were it not for you!!  Ruthie, your support and example are more than inspiring.  And B.... you're always there, for whatever it takes! 

And to all of those who think you can't...  Yes, you can!!!  Whatever it takes.

~ love and gratitude, les

Wednesday, May 16, 2018

In melanoma, if you are worried about your PD-L1 level....DON'T wig out yet!!!!


While a wide variety of folks have been gettin' folks fired up about the presence or absence of PD-L1 expression in relation to response to immunotherapy (checkpoint inhibitors)...there's this:

Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden.  Morrison, Pabla, Conroy, et al.  J Immunother Cancer. 2018 May 9.  
Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma.  
Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8+ T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario.
PD-L1 positivity greater than or equal to 1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity.

In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden.


Immunotherapy works in about 40% of melanoma patients, if you are talking about anti-PD-1 (Nivo/Opdivo or Pembro/Keytruda) and we REALLY need to figure out how to make that response rate better.  Here, researchers from 8 facilities looked at a lot of factors ~ PD-L1 expression, CD8 T cell infiltration, tumor mutational burden and other funky immune factors.  After examination of 231 patients (as best as I can tell), while PD-L1 positivity "correlated with response and OS...but demonstrated limited predictive performance."  "Comprehensive immune profiling demonstrated higher sensitivity (72%) compared to PD-L1 (34%) and tumor mutational burden (32%)."

Clearly, the presence of PD-L1 on your tumor is not the end all be all in determining response to immunotherapy.  Would that it were that simple!  But, y'all know melanoma don't play that way!!  Hang in there ratties!  - c

Friday, May 11, 2018

Sew Chaotically! - Another faux wrap dress, but coral and for Roo!!! M6884


Sew!!!  I plowed through my purple period with this little ruched knit top, M6282 and a cute mesh exercise top, M7610 for Roo!  Now for a coral cornucopia!!


First up is the faux wrap dress, middle left.  I made this one for myself a while back: 

Faux wrap dress - M6884

The pattern is super straight forward and though I had lowered the placement of the "tie" on mine, as it is placed rather high for most reviewers and I am tall, once I had Rose try on mine, I moved it back up almost to where the pattern places it for her.





And since neither of us are all about those bows, after a few wears, I removed them from mine, cutting off some length from the ties and adding snaps to attach them at the side.  Should I make this dress for myself again, I will probably leave the ties off entirely, but Rosie liked them on hers and followed suit with a hidden closure on the left side.

I think it looks so pretty on her!  She was even a good sport and let me snap a quick pic just after she rushed in from work as we were zooming out to our weekly Barre Cardio class!!!  The material is a very soft, lush, almost sweater knit and a little thicker than is comfortable for the season currently.  It will serve her well when school restarts in the fall!!  Part 2 of my coral cornucopia coming soon!  Sew chaotically! - les

Thursday, May 10, 2018

X4P-001, an oral CXCR4 inhibitor for melanoma, Phase 1 study examines results when given alone vs with pembro


Early days for this one...but, there's this:

X4P-001, an orally bioavailable CXCR4 antagonist, enhances immune cell infiltration and activation in the tumor microenvironment of melanoma.  Andtbacka, Pierce, Campbell, Yushak, et al. AARC April 2018.

The CXCR4/CXCL12 pathway plays a central role in the trafficking of key immune cells in the tumor microenvironment (TME). X4P-001 is an oral, selective, allosteric CXCR4 inhibitor. We hypothesize that the disruption of CXCR4/CXCL12 signaling by X4P-001 will favor an improved response to checkpoint inhibitors by modulating the immune cell profile within the TME and increasing CD8+ T cell infiltration. A biomarker-driven phase 1b clinical study is being conducted in melanoma patients to test this hypothesis (NCT02823405).

The primary objectives for the study are to evaluate the safety and tolerability of X4P-001 as a single agent and in combination with pembrolizumab in patients (pts) with metastatic melanoma, and to characterize the effects of X4P-001 alone and in combination with pembrolizumab on tumor immune cell infiltrates. Serial biopsies of cutaneous or subcutaneous melanoma lesions, peripheral blood mononuclear cells (PBMCs), and serum samples were collected pre-dose, after 3 weeks of X4P-001 treatment, and after 6 weeks of combination treatment. Biopsies were assessed by immunohistochemistry (IHC) and multiplexed immunofluorescence (mIF) for multiple markers, including CD3, CD8, FoxP3, PD-L1 and Granzyme B, and by NanoString® analysis for changes in gene expression. PBMCs were analyzed by flow cytometry for both lymphoid and myeloid cells. In addition, multiple serum markers will be assessed using the multi-analyte profile (MAP) platform.

As of September 15, 2017, 13 pts have been enrolled, and 11 have completed the study. The median age was 73 years (range 53-90). Of the evaluable pairs of biopsies, X4P-001 treatment alone increased CD8+ T cells, increased granzyme B signal, increased antigen-presenting machinery such as HLA-DR, and increased IFN-gamma gene expression signature scores in the TME. These biomarker responses were further enhanced when X4P-001 was combined with pembrolizumab. X4P-001 was well tolerated. AEs assessed as related to either X4P-001 or pembrolizumab at any time were diarrhea, maculopapular rash, fatigue, chills, and acute kidney injury. These data, along with additional biomarker measurements, will be presented.

Evidence of enhanced immune cell infiltration and activation is observed in the TME with X4P-001 treatment alone. Increased IFN-gamma gene expression signature scores after single-agent X4P 001 treatment support the use of X4P-001 to increase the likelihood of a response when combined with anti-PD-1 therapy. X4P-001 as a single agent and in combination with pembrolizumab is generally safe and well tolerated. Further in-depth biomarker analysis is ongoing as enrollment nears completion. 

So, real live ratties with metastatic melanoma (though there are only 13 of them, as of this report and only 11 had completed the study) were given X4P-001 alone or with pembro.  Samples of their tumor along with blood tests looking at the immune response were done before the drug, as well as at 3 and 6 weeks into treatment.  Researchers report that they saw increased activation and efforts by the immune system in the tumor microenvironment.  Because of this, they are hopeful that by giving X4P-001 with pembro, the likelihood of a response will be increased.

So...yes.  Early days and few patients examined on this one so far...but, here's hoping!  - c

Tuesday, May 8, 2018

When there is beauty....


...enjoy.



And when your love and best friend knows just what you need...even better.  Thanks B.  Love and hugs to each of you. - les