Thursday, July 19, 2018

PEG-arginase and complete remission in immunotherapy-resistant melanoma, a case study

While the relatively recently approved treatment options for melanoma (both targeted and immunotherapy) have been absolutely life saving for many, myself included, there are still far too many of us in need of something else!!!  To that end, here is a case study...

To begin, PEG is polyethylene glycol, a vehicle used to make things soluble in water (or the human body) so that a drug/substance can be administered.  It is use in PEG-interferon, for example.  Arginase is an enzyme that breaks down arginine.  Arginine is an essential amino acid needed for protein synthesis.  It is used in the liver, for example, to help excrete ammonia.  Strangely, some melanoma cells are unable to synthesize their own arginine, making them dependent on arginine from other cells.  So now...there is this:

Metabolic therapy with PEG-arginase induces a sustained complete remission in immunotherapy-resistant melanoma.  De Santo, Cheng, Beggs, et al. J Hematol Oncol. 2018 May 18.

Metastatic melanoma is an aggressive skin cancer with a poor prognosis. Current treatment strategies for high-stage melanoma are based around the use of immunotherapy with immune checkpoint inhibitors such as anti-PDL1 or anti-CTLA4 antibodies to stimulate anti-cancer T cell responses, yet a number of patients will relapse and die of disease. Here, we report the first sustained complete remission in a patient with metastatic melanoma who failed two immunotherapy strategies, by targeting tumour arginine metabolism.


A 65-year-old patient with metastatic melanoma who progressed through two immunotherapy strategies with immune checkpoint inhibitor antibodies was enrolled in a phase I study (NCT02285101) and treated with 2 mg/kg intravenously, weekly pegylated recombinant arginase (BCT-100). The patient experienced no toxicities > grade 2 and entered a complete remission which is sustained for over 30 months. RNA-sequencing identified a number of transcriptomic pathway alterations compared to control samples. The tumour had absent expression of the recycling enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC) indicating a state of arginine auxotrophy, which was reconfirmed by immunohistochemistry, and validation in a larger cohort of melanoma tumour samples. 

Targeting arginine metabolism with therapeutic arginase in arginine auxotrophic melanoma can be an effective salvage for the treatment of patients who fail immunotherapy.

For what it's worth! - c

Friday, July 13, 2018

Sew (and live) Chaotically! ~ TURTLES!!! ~ made up in a Hollyburn skirt and a Polly Top to go with!!!

First....there was melanoma.  Then - there was Sally!!!

Here's the back story:  Inauspicious Beginnings

And the pics:  Sally the Loggerhead Turtle

And more pics:  Beach Scenes

Yes, turtles (and dragonflies) are now an intrinsic part of my life and part of the fiber of my family and friends.
Yentle Garden, around Yertle Creek, sports its own turtle (X's 3!!) figurine!  Creek designed by nature, but controlled and turned into a beautiful garden by Roo (aka Yentle!!  HA!).  Here's one of it's early pics:  The tree
More recently, the turtles continue!  As I turned into the drive just the other day, I glanced over to the new garden plot we've added and this is what I saw!  I laughed out loud!  B is one crazy dude, but very good at watering my plants, tolerating my whims, and ever so cute in his bow ties!!! 
Then, a few months ago....I got this beautiful surprise!!!
It was from Ruthie!  She does the BEST wrappings!!!!!  
They are always beautiful, perfectly match their contents, and contain the most amazing gifts!!!  Look at this TURTLE fabric!!!!
Sew ~ after pondering my precious turtle fabric for a bit, its destiny became clear.  I decided it would make a perfect Hollyburn skirt (Sewaholic) and needed a little Polly Top  (By Hand London) to go with! The Polly is bound with my own bias binding and the basic quilting cotton (chosen because I liked the color combo) did not like being eased into the curved bodice, wanting to gather instead.  I let it be, leaving some gathers evenly placed at the curves!  I cut the front of the Hollyburn skirt on the fold rather than in two pieces as prescribed by the pattern, so that I could place my turtles just so!!!  Had to shave off and reshape the sides a bit, but I think it worked!!!  Used my self constructed contoured waistband as mentioned in the post above.
The turtle fabric has the perfect attitude and drape for this skirt!!  
With fabric this fab, waste not want not!!!  There is a special baby on the way, where the love and longevity of the turtle plays a beautiful role as well!!!  May this turtle pillow provide cozy comfort for nursing, rocking into sweet dreams, and stories in the days to come!
With much love, my turtle collection continues to grow - all the bounty:  A turtle a day...  
And Ruthie hits a home run again with Miss Flora, nestled front and center!
Roo got a special prize, too!  It was right up her Owl-ly!!!!  Ha!  Are her flowers not beautiful????
With Ms. Turtle living just beneath!
Sometimes life is a beautiful circle that defies anticipation or explanation ~ requiring only our belief in others, love, and...well, turtles!!!   -  love, les

Wednesday, July 11, 2018

VISTA - an independent negative prognostic factor, but possible avenue for intervention, in melanoma...

As the search continues for ways to predict response and new avenues to attain a response in the treatment of melanoma - there is this:

VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival. Kuklinkski, Yan, Li, et al. Cancer Immunol Immunother. 2018 May 8.

Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson's correlation coefficients identified associations in expression between VISTA and myeloid infiltrate and the density of PD-1+ inflammatory cells. The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis and multivariate analysis. Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.

Get busy researchers!!!  - c

Saturday, July 7, 2018

Circulating tumor cells/DNA in melanoma!!! Have I not mentioned this a ZILLION times????

There are many blood (and other fluid) markers, all much easier to collect that actual tumor samples, that can be used to diagnosis melanoma, determine tumor type, prognosis and response to therapy.  Here's a link to zillions of posts:  Neutrophil-to-lymphocyte ratio and outcomes in melanoma. Yep, AGAIN!!!!!  More here:  Simple blood tests that tells us where we are with our melanoma....AGAIN (and again, and again, and again)!!!

And there is this (with tons of links within) on circulating tumor cells/DNA alone:  ASCO 2017: Circulating DNA to measure response in melanoma

Now, these:

Circulating Tumor Cells in Stage IV Melanoma Patients. Hall, Ross, Bowman, et al.J Am Coll Surg. 2018 May 7.
Management of stage IV melanoma patients remains a challenge. In spite of promising new therapies, many patients develop resistance and progression. The aim of this pilot study was to determine if CTCs are associated with shortened (180-day) progression-free survival (PFS) following a baseline CTC assessment in stage IV melanoma patients.

A baseline CTC assessment was performed in 93 stage IV melanoma patients using a commercially available immunomagnetic system. The presence of greater than/equal to 1 CTC was considered a positive result. A Cox multivariable regression model was used to evaluate the association between presence of CTCs at baseline and PFS, after adjusting for covariables. Kaplan-Meier curves and a log-rank test were used to summarize and compare unadjusted PFS for patients stratified by CTC positivity.

Median follow-up was 17 months; mean age was 55 years. Thirteen of 93 (14%) patients had no evidence of disease (NED) at baseline CTC assessment. One or more CTC was detected in 39/93 (42%) of patients at baseline. CTCs were not associated with primary melanoma features or NED status. Twenty-eight of 93 (30%) patients progressed within 180 days of baseline draw, with 20/39 (51%) of the CTC positive patients relapsing compared to 8/54 (15%) of the CTC negative patients. In adjusted Cox models, a significant association was found suggesting worse PFS within 180 days for CTC positive patients at baseline (vs. CTC negative).

One or more CTCs at baseline were associated with progression within 180 days in stage IV melanoma patients. This information warrants further study of CTCs as a means of identifying patients at high-risk for disease progression.

Measuring circulating tumor cells can predict response and progression!! And, this.....

Quantitative monitoring of circulating tumor DNA predicts response of cutaneous metastatic melanoma to anti-PD1 immunotherapy.  Herbreteau, Vallee, Knol, et al. Oncotarget. 2018 May 18.

Immunotherapies have changed the medical management of metastatic melanoma. However, the early detection of patients who do not respond to these treatments is a key issue. We evaluated the quantitative monitoring of circulating tumor DNA (ctDNA) as an early predictor of response to anti-PD1. Patients treated with anti-PD1 for metastatic mutated melanoma were selected. The somatic alteration detected on the tumor tissue was quantified on plasma DNA by digital PCR (dPCR) at treatment initiation, after 2 and 4 weeks of treatment, and then every 4 weeks until progression. The absence of biological response (defined as a significant decrease in the amount of ctDNA relative to the baseline level) after 2 weeks of treatment was associated with a lack of clinical benefit under anti-PD1. In the presence of a biological response at week 2, detection of subsequent biological progression (significant increase in the amount of ctDNA relative to its nadir) was 100% predictive of progressive disease, on average 75 days prior to radiological detection. Patients with a persistent biological response beyond week 16 did not experience any progressive disease and exhibited sustained responses. In conclusion, we show that quantitative monitoring of ctDNA, using criteria accounting for dPCR measurement imprecision, allows the early and specific detection of patients who do not respond to anti-PD1 therapy.

When circulating tumor DNA was monitored in patients treated with immunotherapy, no significant decrease in the ctDNA measured in the blood was associated with lack of benefit from anti-PD-1 AND an increase in the ctDNA "was 100% predictive of progressive disease, on average 75 days prior to radiological detection."  Think what being able to change treatments, from one that is not working to one that might serve you better, 75 days sooner, could mean for patient outcomes!!!  And, there's this:

Evaluating Circulating Tumor DNA From the Cerebrospinal Fluid of Patients With Melanoma and Leptomeningeal Disease. Ballester, Glitza, Douse, et al.  J Neuropathol Exp Neurol. 2018 Jun 4.  

Circulating tumor DNA (ctDNA) refers to tumor-derived cell-free DNA that circulates in body fluids. Fluid samples are easier to collect than tumor tissue, and are amenable to serial collection at multiple time points during the course of a patient's illness. Studies have demonstrated the feasibility of performing mutation profiling from blood samples in cancer patients. However, detection of ctDNA in the blood of patients with brain tumors is suboptimal. Cerebrospinal fluid (CSF) can be obtained via lumbar puncture or intraventricular catheter, and may be a suitable fluid to assess ctDNA in patients with brain tumors. We detected melanoma-associated mutations by droplet-digital PCR (ddPCR) and next-generation sequencing in ctDNA obtained from the CSF (CSF-ctDNA) of melanoma patients with leptomeningeal disease. There is a strong correlation between mutation detection by ddPCR, the presence of circulating tumor cells in CSF and abnormalities in the MRI. However, approximately 30% of CSF samples that were negative or indeterminate for the presence of tumor cells by microscopic examination were positive for CSF-ctDNA by ddPCR. Our results demonstrate that CSF is a suitable fluid for evaluating ctDNA and ddPCR is superior to CSF-cytology for analysis of CSF in melanoma patients with leptomeningeal disease.

Here researchers are simply noting that the cerebral spinal fluid can be monitored in the same manner blood samples can be.

I have been noting these reports for YEARS!!!!!!!!!!!!!!!!!!  If I am aware of these options, then oncologists should know about these study results and assay possibilities far better than I.  These minimally invasive, but highly informative tests, should be readily available and utilized as part of the arsenal to diagnosis, predict response, determine progression, find appropriate therapy, and ultimately save lives of melanoma patients ~ TODAY!!!!  - c

Wednesday, July 4, 2018

Skin resident memory CD8+ T cells, stimulated by vaccines, protect against melanoma!!!!

I have long hoped vaccines would play a positive role in melanoma treatment!!  Heck, I was a rattie in one of the arms of my nivo trial that included peptide vaccines.  Here is one of my latest posts on the topic:  ASCO 2018!!! We'll start with melanoma vaccines....and a story!

To sum up that post ~ I, along with my fellow ratties, were injected with 6 painful peptide vaccines (as in, they were administered as an injection into our thighs) every 2 weeks for 6 months along with our intravenous infusion of nivolumab.  It turned out that our particular vaccine did us no good.  It is even possible that the injections "sequestered" our helpful CD8+ T cells at the site of the injections.  There is some evidence that rather than revving up our fighting T cells and having them go attack our melanoma, the vaccines simply attracted them, perhaps even fired them up, but then the little suckers just lazed about at the vaccine sites, like camels at an oasis.  (Do camels do that?  I don't really know.)  Anyhow, additional abstracts about vaccine hopes and dreams and scams are included in the post, but... there is also 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....

Okay.  I think this is the perfect place to utilize a phrase I created in my childhood, "What's so about that?????"  Well, maybe nothing.  But now, there's this - (and a link to the entire article if you are so inclined):

Vaccination-induced skin-resident memory CD8+ T cells mediate strong protection against cutaneous melanoma

Vaccination-induced skin-resident memory CD8+ T cells mediate strong protection against cutaneous melanoma. Gálvez-Cancino, López, Menares, et al.  Oncoimmunology. 2018 Mar 19.

Memory CD8+ T cell responses have the potential to mediate long-lasting protection against cancers. Resident memory CD8+ T (Trm) cells stably reside in non-lymphoid tissues and mediate superior innate and adaptive immunity against pathogens. Emerging evidence indicates that Trm cells develop in human solid cancers and play a key role in controlling tumor growth. However, the specific contribution of Trm cells to anti-tumor immunity is incompletely understood. Moreover, clinically applicable vaccination strategies that efficiently establish Trm cell responses remain largely unexplored and are expected to strongly protect against tumors. Here we demonstrated that a single intradermal administration of gene- or protein-based vaccines efficiently induces specific Trm cell responses against models of tumor-specific and self-antigens, which accumulated in vaccinated and distant non-vaccinated skin. Vaccination-induced Trm cells were largely resistant to in vivo intravascular staining and antibody-dependent depletion. Intradermal, but not intraperitoneal vaccination, generated memory precursors expressing skin-homing molecules in circulation and Trm cells in skin. Interestingly, vaccination-induced Trm cell responses strongly suppressed the growth of B16F10 melanoma, independently of circulating memory CD8+ T cells, and were able to infiltrate tumors. This work highlights the therapeutic potential of vaccination-induced Trm cell responses to achieve potent protection against skin malignancies.

You may be thinking, "Interesting, I guess!  But, what's so about that????"

Well, the notation "intradermal" might just be the thing.  It seems from this research that in order to elicit the response Galvez and Lopez are talking about, the vaccine had to mess with the SKIN!!!  Not just be stuck in the body else wise.

Now, give me a minute here.  Remember the mad scientist I live with???  He has been postulating a theory about how triggering a response in dendritic cells and CD8+ T cells that LIVE IN THE SKIN might be the ticket to stimulating the development of vitiligo and thereby a good response AGAINST melanoma for years!

Remember this?  Itching and vitiligo associated with progression free survival after Pembro/Keytruda???!

And this from 2014:  Vitiligo and melanoma  Which includes this commentary:  What I think this says is:  The CD8+ T cells that cause vitiligo, promote response to melanoma.  But, we don't know how. So...the researchers checked a certain type of T cell in mice with no thymus (so the mice couldn't use that part of the process to induce vitiligo) and even so, the active T cells continued to produce vitiligo and protection against melanoma.....and they don't know why!

This from 2015:  Vitiligo....a good prognostic indicator for melanoma!  Which, for the purposes of this discussion is most important for this pic and the commentary beneath it ~

"Vitiligo initiation at site of surgery."  The vitiligo in this poor actual rattie started WHERE THE SKIN WAS CUT!!!!!!!!!!!!!!!!!!!!!

And finally - if you are still with me!!! - there is this from 2011:  Anti-PD-1 is still kicking....

Here, I note:  Apart from that, Brent is developing a rather complicated theory about why which rats, both human and rodent, develop vitiligo, versus those who do not, and thereby have a more positive outcome in regard to their melanoma.  It has to do with the dendritic cells in the skin, their exposure to the melanoma antigen (either from vaccines or from tumor material itself), and the subsequent triggering of the immune response.  I'm telling you...the man is going to win the Nobel Prize for finding the answer to this mess!!  But bottom line, if he's right...does this mean I should be grateful that I am thin, thereby lacking in significant subcutaneous tissue into which the vaccines should have been injected?  Thankful that vaccine material drifted into my dermis either by chance or poor administration techniques by some of the administrators?  Remember Ruthie's dismay when tons of my "Elmer's Glue" came oozing back out of my injection sites? I can't answer those questions, but I'm betting Bentie will figure it out.  I'll just keep reporting.

Okay.  You made it!!!  What all this means, I am not entirely certain.  But, I think research is building more and more of a case about how the skin itself harbors not only evil cutaneous melanoma cells for some of us, but also the key to removing melanoma's protective shroud and killing it!!!  We know that the skin contains:  dendritic cells (of many types!!!), gamma T cells, alpha T cells, CD8+ T cells (specifically the trm [tissue resident memory] cells addressed in this most recent abstract).  We also know that Tissue Resident Memory cells travel up to 2mm per day in the intradermal space.  That's not totally weird or creepy, is it??? TRM's, surveying their territory like a sand shark along the beach, on the look out for tasty minnows or melanoma cells!  Perhaps, the horror of injections that hurt like a booger, then oozed the nasty thick white goo back OUT of the holes poked in my skin, DID make a change in some of my dermal CD8+ Tissue Resident Memory cells.  MAYBE those vaccines did help trigger my vitiligo, as an outward sign of an interior response by my CD8+ T cells against my melanoma.  Maybe the vaccines I was given did not work as initially intended, but did, perhaps, play a role in why I am still here.

Happy 4th.  Here's hoping your dendritic and CD8+ trm cells are busy bees today and every day!!! - c