CD40 Antibody therapy for melanoma....another way to activate the immune system?

CD40 is a positive signaling molecule (a co-stimulatory protein found on antigen presenting cells). It turns T-cells on.  It does not "take off the brakes" like anti-PD1 does, rather it "turns on the gas" to the immune system.  It appears that in this particular patient...after administration....the cancer was gone and a new set of T-cells developed.

Immune activation and a 9-year ongoing complete remission following CD40 antibody therapy and metastaectomy in a patient with metastatic melanoma.
Bajor, Torigian, Mick, et al.  Cancer Discov. 2014 Sep 24.

Direct immune activation via agonistic monoclonal antibodies is a potentially complimentary approach to therapeutic blockade of inhibitory immune receptors in cancer. Patient with metastatic melanoma was given an agonistic CD40 monoclonal antibody, underwent removal of a  single met and achieved a complete remission ongoing for more than 9 years after starting therapy.  Tumor microenvironment after immunotherapy was associated with  pro-inflammatory modulation and emergence of a de novo T-cell repertoire as detected by next-generation sequencing of T cell receptors in tumor and blood.  The de-novo T cell repertoire identified in the post-treatment met sample was also present - and in some cases expanded - in the circulation years after completion of therapy.

There is a fair amount of info lacking in this report.  How was CD40 administered? (I assume IV.)  For how long?  How often?  Side effects?  The implication (though not stated) is that only one met was removed and perhaps others resolved spontaneously due to the now stimulated immune system...though that is unclear.  However, I thought the process was interesting and perhaps more info and studies in this direction will occur in the future.


Yours, c

Anti-PD1, Nivo and Pembro, as first line drugs!!! From the experts....

So many have been terribly disappointed with the FDA requirements that you must first fail ipilimumab (Yervoy) as well as BRAF inhibitors, if your melanoma is BRAF positive, BEFORE you can be given Pembrolizumab (Keytruda)...at least if you want insurance to pay for it...and at $12,500 per month/$150,000 per year, I don't know who could afford that price tag on their own!!!

But here's what the experts say about what is coming with anti-PD1 drugs in the future!!!!

Although pembrolizumab was approved in the second-line setting, melanoma experts believe that the PD-1 blockers have a bright future in the first-line setting. “With pembrolizumab, patients have a 25% to 35% response rate,” Dr. Weber said. “If you are a BRAF wild-type patient, the maximum [response rate] with ipilimumab is 15% to 20%.” He pointed out that the FDA and the European Medicines Agency will only approve a drug in a setting that is supported by data, and so far, Merck has only submitted second-line data. This, however, will change.
“There is an ongoing pembrolizumab versus ipilimumab trial in treatment-naive patients. There is a first-line nivolumab trial: ipilimumab versus nivolumab versus combo ipilimumab and nivolumab,” Dr. Weber said. “Each trial has an active-control arm (not placebo), so we are going to be waiting a little bit to see the results, but if those trials are positive, which I feel confident they both will be, the FDA will approve the anti–PD-1 drugs in the front-line [setting]. In the future, I would bet you good money that everybody is going to use PD-1 drugs first and ipilimumab later.”

Check out this link from Clinical Oncology News, October 2014...and read it for yourself!

PD-1 Blocker Class Will Shake Up Melanoma Treatment 

Fingers crossed that anti-PD1 as a first line drug for melanoma will be a reality sooner rather than later!!!  Best - c

She IS that person!!!

Cleaning for a reason!!!!

Check out the link above. You think there's nothing you can do?  You think, 'Oh, I would help, if I could."  She did.  You can.

As for me...Still looking.  Still trying.  But...I do have this...today...

"I have come to this site for hope countless times. Hoping this post helps someone like you all have helped me. A shout out to Celeste who originally planted the seed regarding this trial.
CT scan today (8 wks out) show 30% reduction in liver lesions. 
Thank you.
Angela"

Does it really matter what others think about you?  What matters?  Why did this post to MPIP make me cry? I don't know.  Because melanoma sucks?  Because her husband's doc should have told her about the trial?  Because I'm crazy?  Because...those that SHOULD don't.  I don't know.  
But, I am trying.  Love - c

The person I want to be....

Are you this person? Am I? Could I be?

Doing little things can do so much!!!  Love - c

Biochem....eval of longterm results in melanoma

Folks still ask about "biochem"....it has positives and negatives like all melanoma treatments with roughly a 6% response rate....some docs still recommend it....so here is some data, recently tabulated...

Biochemotherapy with interleukin-2 for metastatic melanoma:  Long-term results in 100 patients
Abstract 9047 ASCO 2014  Minor, Kashani-Sabet, et al.

Retrospective single-institution review of 100 patients who began therapy between 9/30/2002 and 6/20/2006.  Median f/u = 9 years. Patients had O'Day treatment, similar to ECOG BC except Temozolomide is used for DTIC;  6 cycles of BC, not 4; decrescendo IL-2 dosing 36-18-9-9 miu/day dosing not based on BSA; and patients received maintenance in patient "pulse IL-2" 108miu/42 hours monthly for 6-18 months after BC.
Results: 
28 patients are still alive, all NED.
One patient died due to a pulmonary embolus, one died from sepsis during BC, and 70 died for metastatic melanoma.
17 achieved CR with BC and never relapsed.
2 achieved PR, had surgery for solitary sites of residual disease, and are NED.
2 patients had late relapses over 3 years after BC.  The first received ipi and is now NED off therapy.  The second responded to ipi, progressed and is now NED on anti-PD1.
One patient received BS in 2005, relapsed in 2007, and is NED after multiple continuous treatments over 7 years with chemo, RT, surgery, ipi and vemurafenib.
Of the 28 patients alive, only the last two are currently receiving therapy.
CONCLUSION:  First-line decrescendo BC can give durable remissions, late relapses are uncommon.  Durable response to ipi may follow progression with BC.  Biochemotherapy should now be systematically studied as second line or consolidation therapy.

Hope it helps.  c

Death With Dignity? Timshel.

"...the Hebrew word, the word timshel - 'Thou mayest' - that gives a choice.  It might be the most important word in the world.  That says the way is open.  That throws it right back on man.  For if - 'Thou mayest' - it is also true that 'Thou mayest not'." ~ John Steinbeck.  East of Eden

The concept of death with dignity, in all its permutations, is something I've given a good deal of thought....as a health care provider....as a patient.  I have witnessed patients and their families endure horrible indignity and pain that make it clear...there ARE fates worse than death.  I have experienced enough suffering and seen first hand the potentially devastating effect my own diagnosis could carry such that I know I intend to keep my options open.  I have experienced the loss of friends, by their own hands, in sad, lonely circumstances...making me achingly wish that they had felt they had had better options available.  My decisions are mine.  They are not to be dictated by anyone other than myself.  Likewise, choices made by others are theirs alone.  I have no right to make their lives, or deaths, more difficult than need be.

The links below attach the the incredible stories of three amazing women.  All links include audio and written versions.  I encourage you to peruse both, but the audio brings their voices and the voices of their family home....to your heart.

Brittany, a 29 year old with Stage IV glioblastoma, moved with her family to Oregon in order to legally utilize the Death with Dignity Act which allows voluntary self-administration of lethal medications, prescribed by a physician, expressly for that purpose.  Here is her story, her family's thoughts, her reasons.....
Brittany-Maynard-death-with-dignity-compassion-choices via People

Kara was diagnosed with breast cancer at age 36, now Stage IV.  She is profoundly religious, views her struggles as a gift from God in order to draw nearer to him and share his love with others and strenuously opposes the act of suicide even when a disease process is obviously no longer compatible with life.  Her story....
A response from Kara Tippetts, mother of 4 dx'd with breast cancer at 36

This NPR report shares the story of Sandra Bem, psychologist and professor at Cornell, as well as prior volunteer for a suicide hotline.  She enacted her plan to self-administer a lethal dose of medication once her diagnosis of Alzheimers had rendered her unable to remember much of her own life or follow a movie plot more complicated than Mary Poppins...but BEFORE she lost the ability to recognize and communicate with her family.  Here is her story....told by her husband and adult daughter...with their thoughts and love...before, during, and after...
http://www.npr.org - how-a-womans-plan-to-kill-herself-helped-her-family-grieve

It is interesting that included in the report above are the study findings noting families dealt with the death of a loved one who chose death by assisted suicide slightly better than families whose loved ones died of natural disease progression.  The investigator notes that the cause of death was most likely NOT the determining factor....but rather "because the dying person prepared their family for the inevitability of their death."

Timshel. - c

Slides from Paris Melanoma Meeting addressing ipi combos

Covering much of the same territory as my prior post  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/09/weber-presentation-on-present-ipi.html
However, this presentation is in slide form, allowing you to see the data a bit differently.  Here is a synopsis with presentation linked below:

For ipi and nivo...combo or sequential:

• 43% ORR with 17% CR's and 82% in remission for all concurrent ipi/nivo patients
• 62% grade 3-4 AEs (LFTs, lipase, amylase, rash, colitis)
• BRAF status, PD-L1 tumor staining NOT associated with response
• Response in sequential patients associated WITH ipi PK levels prior to starting anti-PD1
• Concurrent 2 yr OS 79% = "IMPRESSIVE" 

Eval of T-VEC (Talmogene Laherparepvec) and ipi combo:

• Unresected, untreated Stage IIIB/IV, 18 patients
• 4 CR, 6 PR, 3 SD, ORR = 56%
• Only 3 grade 3-4 AEs from ipi
• Results may address the hypothesis that T-VEC may prime an immune response amplified by ipi

INCBO24360 and ipi:

• Target inhibition of IDO achieved at 25-50mg BID
• 33% RR and 33% stable disease
• Toxicity = increased LFTs
• Immunotherapy naive patients did best
• 10 of 12 patients required no further therapy

Nivo in patients naive to OR progressed on ipi:

• NO diff between ORR, PFS, and OS between ipi naive and ipi refractory patients [This is different from what studies have shown with Keytruda! More info on above post.]
• High pretreatment MDSC (myeloid derived suppressor cells) increases in T-regs associated with poor outcome [better explanation of this on blog post linked above]
• Perhaps combining anti-PD1 with MDSC or T-reg depletion would make it more effective

Paris Melanoma Meeting July 2014

Wishing all the ratties my very best! - c

Girl power...and the Nobel Peace Prize!!!!

Malala Yousafzai of Pakistan and Kailash Satyarthi of India, were awarded the Nobel Peace Prize for their struggle against the suppression of children's rights...specifically their right to an education. At age 17, Malala is the youngest person ever to win the prize.

See my review of her story in my August 14, 2014 post!

I especially love that Malala was in chemistry class when her teacher pulled her aside to tell her that she had won! She reportedly views the the bestowing of the prize to a young female Pakistani Muslim and a 60 year old male Indian Hindu - as "a message of love between Pakistan and India, and between religions...it means we are standing together to ensure all children get a quality education."

An amazing young woman to be sure!!! What were we doing when we were 17? Never mind! What girls are doing...and being allowed to do....and prevented from doing...and being encouraged to do...are the things that matter now!

Girl in a country song!

Let girls learn!

Ban Bossy

Let's go girls!!! - c

Another antibody-Drug Conjugate for melanoma

For a little background and explanation here's a blurb from a prior post...

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."

The full post gives more data about this particular ADC, their history in general, and the one discussed in the article below:  new-treatment-for-melanoma-adc's

A dear one of mine participated in the trial noted in that post and while the therapy did diminish some of his tumor burden and gave him about a year in which to find a new treatment before growth of tumors resumed....it was not a panacea.  The "bad ass cytotoxin" leached more into his system than one would hope a REAL Trojan Horse would allow.  He did suffer a good deal of fatigue, hair loss, and significant neuropathies that, while improving now, are still somewhat troubling.  At any rate, here is a study of an older ADC...previously used most in HER-2 breast cancer...that targets the surface protein gpNMB instead of Endothelin B, but does use the same bad boy cytotoxin - auristatin E...being utilized as treatment for melanoma patients.

Phase I/II study of the antibody-drug conjugate Glembatumumab Vedotin in patients with advanced Melanoma.  Ott, Hamid, Pavlick, Sznol, et al.  J Clin Oncol. 2014 September 29.

"The antibody-drug conjugate glembatumumab vedotin links a fully human immunoglobulin G2 monoclonal antibody against the melanoma-related glycoprotein NMB to the potent cytotoxin monomethyl auristatin E."  117 patients were given glembatumumab vedotin every 3 weeks (in a dose escalation and phase II expansion with three different dosing levels).  Grade 3/4 toxicities that occurred in 2 or more patients were:  rash, neutropenia, fatigue, neuropathy, arthralgia, myalgia, and diarrhea.  3 treatment related deaths occurred at doses exceeding what was determined to be the maximum tolerated dose (MTD) due to pneumococcal sepsis, toxic epidermal necrolysis and renal failure.  In the schedule I, phase II expansion cohort (n=34):  5 patients (15%) had a partial response, 8 (24%) had stable disease for more than 6 months.  The objective response rate was 2 of 6 for the schedule 2 MTD and 3 of 12 for the schedule 3 group.  Rash was correlated to greater overall response and improved progression-free survival.  "CONCLUSION:  Glembatumumab vedotin is active in melanoma. The MTD (1.88mg/kg once every 3 weeks) was associated with a promising overall response rate and was generally well tolerated.  More frequent dosing was potentially associated with a greater overall response rate but increased toxicity."

I still very much like the idea of antibody drug conjugates.  But, the "bad ass cytotoxin" is not as linked as we would like it to be.  I fear we have a long way to go!  Merci mille fois!!!.... to J and all the other ratties who teach the rest of us so much.  Much love - c

How am I?

I really can't complain!  I've been feeling well.  Very few arthralgias or mouth ulcers these days.   Rashes remain pretty itchy and frequent. Occasionally, there are red flares to my peptide injection sites, but they are itchy, not at all painful.  I spent the past 6-9 months working a good bit extra, but am now able to cut down to twice weekly 12 hour shifts, so that will be nice for a bit.  I run 2-4 miles on most off days. Once a week Roo has me doing speed work with her, where she pushes my times below 8 minute mile pace. When she does her 10+ mile runs (Crazy girl is training for another 1/2 marathon!!) I have been biking with her.  Having fun with my various sewing, crocheting, cooking, gardening, and reading projects...as ever.  Love my precious time with family and friends.

  

Summer dresses AND summer flowers!

Contrasting afghans for two special girls!

 And there's gotta be a couple bow ties for B!!

Spending some time pondering... If this is the beginning of more time....how do I make the very most of it?  What can I do that needs to be done???  So, yeah....I guess this about sums it up!!!!

It can't get much better than this, now can it?  Wishing you each my best!!! - c