Sunday, July 5, 2020

Intratumoral (intralesional) therapy and a new guy in town: IL-12 Plasmid Transfection (tavo) with pembro

I've been a fan of incorporating intratumoral/intralesional therapy into melanoma care for some time.  Here's proof:  A zillion articles on intralesional therapy

Now this ~

Intratumoral Immunotherapy-Update 2019.  Hamid, Ismail, Puaznov.  Oncologist.  2020 Mar;25.

Intratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis, followed by release of tumor-derived antigens and subsequent activation of tumor-specific effector T cells. In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV-10 and toll-like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa-Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types. Talimogene laherparepvec (T-VEC), a genetically modified herpes simplex virus type 1-based oncolytic immunotherapy, is the first oncolytic virus approved by the U.S. Food and Drug Administration for the treatment of unresectable melanoma recurrent after initial surgery. In patients with unresectable metastatic melanoma, T-VEC demonstrated a superior durable response rate (continuous complete response or partial response lasting ≥6 months) over subcutaneous GM-CSF (16.3% vs. 2.1%). Responses were seen in both injected and uninjected lesions including visceral lesions, suggesting a systemic antitumor response. When combined with immune checkpoint inhibitors, T-VEC significantly improved response rates compared with single agent; similar results were seen with combinations of checkpoint inhibitors and other intratumoral therapies such as CAVATAK, HF10, and TLR9 agonists. In this review, we highlight recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on T-VEC in the treatment of advanced melanoma as a model for future solid tumor indications.  This review provides oncologists with the latest information on the development of key intratumoral immunotherapies, particularly oncolytic viruses. Currently, T-VEC is the only U.S. Food and Drug Administration (FDA)-approved oncolytic immunotherapy. This article highlights the efficacy and safety data from clinical trials of T-VEC both as monotherapy and in combination with immune checkpoint inhibitors. This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T-VEC, the only U.S. FDA-approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T-VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.

And this ~

Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma.  Algazi, Twitty, Tsai, et al.  Clin Cancer Res.  2020 May 6.

Tumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).

Tavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done.

The combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFN╬│ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses.

The combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors.

And finally, this ~

Insights Into the Molecular Mechanisms Behind Intralesional Immunotherapies for Advanced Melanoma.  Vidovic and Giacomantonio.  Cancers (Basel) 2020 May 22. 
 The incidence of cutaneous melanoma, a highly malignant skin cancer, is increasing yearly. While surgical removal of the tumor is the mainstay of treatment for patients with locally confined disease, those with metastases face uncertainty when it comes to their treatment. As melanoma is a relatively immunogenic cancer, current guidelines suggest using immunotherapies that can rewire the host immune response to target melanoma tumor cells. Intralesional therapy, where immunomodulatory agents are injected directly into the tumor, are an emerging aspect of treatment for in-transit melanoma because of their ability to mitigate severe off-target immune-related adverse events. However, their immunomodulatory mechanisms are poorly understood. In this review, we will summarize and discuss the different intralesional therapies for metastatic melanoma with respect to their clinical outcomes and immune molecular mechanisms.
For what it's worth.  Hang tough, ratties!!! - c

Thursday, July 2, 2020

Sew Chaotically! ~ Olya!

Spring stayed cooler than usual for a while this year.  This over sized shirt, The Olya by Paper Theory, made up in the softest double gauze from Fabricdotcom, became my perfect comfy staple.  I made up the size 10 with no mods other than omitting the pockets.  

Stay home.  Stay safe.  Wear a mask and keep your distance!!!!   - les

Sunday, June 21, 2020

Always up for it ~ This guy!

No matter how tired, no matter how crazy, no matter his personal preference - this guy was THERE!  Ready for any challenge he or the kiddos could dream up...

The FIRST of sooooo many pumpkins!!!

Yep!  You join the fam - you make a punkin!

So many bait fish collected!  With astonishing sun screen application!!!
So many fierce animals to ride!

Hikes to edges of cliffs, never mind personal concerns about heights!
Always demonstrating serious dedication to silliness!

So much running!!!

And splashing!!!

Yes, these are fierce animals!!!

Definitely up for family eating!
Snow playing.
Special presents.
Being the zaniest family photographer!
The best sous chef!

Always ready for Bancy Falls!
And crazy fun...
And building computers...

Celebrating every moment with the best smile...
...and the biggest heart.
Good thing too, my sweet peeps, cause yo momma ain't ride'n no elephant, running a half marathon, or building a computer!!!!!!  But perhaps the best thing he ever did for you was...

...keep your mother sane!!!  HA!!!  We love you, Bentie.  You are the best daddy ever!!! - les

Thursday, June 11, 2020

And just like that.... sweet zany baby boy...

...has grown into an amazing man, with the kindest heart.

And right on cue ~

~ the Fred Azaleas celebrate his special day.  I love you ever so much, Freddie Froo!!!  Happy birthday. - mommy

Friday, June 5, 2020

Winds of change?

One step backwards, a few steps forward?

Sadly, in my hometown, the statue of Confederate Lt. General A.P. Stewart, defaced in recent protests sparked by the murder of George Floyd outside the Courthouse, will be restored and remain in place.  As recently as 2017, in the midst of an effort to have it removed, county commissioners voted 6-2 to keep it.

In better news, the ginormous statue of Confederate General Robert E. Lee, long a source of pain to black residents of Richmond, Virginia and defaced in recent protests, will be REMOVED!!!!  The irony that this move is led by the governor, a man only 5 years older than I, who somehow thought it was okay to be photographed, while in COLLEGE, in blackface with someone in KKK garb (or vice versa, since to my knowledge he has never admitted which role he took - as if that could slip your mind - though he has apologized) is not lost.  Perhaps I should view this as a hopeful sign that people can learn and change rather than my more natural cynical view that this is token penance.  Either way, I'll take it.

Also wafting forward with the more positive breeze, the monument to Confederate troops in Birmingham, AL was removed this week and the statue to Frank Rizza, the Police Commissioner and Mayor who effectively opposed desegregation from 1972-1980 is to be taken down in Philadelphia.

Slowly we change, but change we must.  Now.  What happened to #chattanoogastrong ??????  Hmmmm?????  This breeze is but the quiet before the hurricane.  A hurricane, that in this case we can prevent if we simply do what is right.  Is the removal of a hurtful monument to the enslavement of our black friends and neighbors and the deaths of 750,000 Americans really that difficult?  What are these monuments here to commemorate exactly?  Think about it, Chattanooga.  ~ les

Monday, June 1, 2020

Real Leadership ~

In this crazy time, real leadership has been hard to find - especially at the pinnacle of our government where it should be the most cohesive, intelligent, and certain to protect the weakest among us.  Longstanding prejudice and systemic racism in this country has affected our black and brown brothers and sisters in ways that damaged their chances for education, economic advancement, basic rights and health.  The ravages of COVID laid all of this bare.  The black men killed by police officers, a small portion of whom I enumerated in my last post, culminating in the murder of George Floyd last week has added incredible fury and fuel to a pandemic of rampant racism and a deadly virus.  Still, there are those who choose to lead.  Many governors, mayors, and yes - even police chiefs - have filled the void and worked to lead us through the ongoing pandemic, the peaceful protests of those who object, demanding change, to the continuation of our racist ways, and the horrible slime who would use this chaotic time to loot and burn.

Yes, even during these times...

These Portland, Oregon officers took a knee in solidarity with protesters.
This police force built bridges, bonding with demonstrators in Flint, Michigan.
And from my own city, Police Chief Roddy issued the statement above, in Chattanooga, TN.
Granted, these are small points of light given the darkness that currently surrounds us.  But, they can light our way, if we let them.  This is what real leadership looks like.  This is where we can draw hope and strength.  This is something we can build on.
Much love to each of you.  ~ les

Wednesday, May 27, 2020

Your life should not be in danger because of the quantity of melanin in your skin!

Ironic title for someone with Stage IV melanoma, no?  But, each day headlines in America, land of the free, proves that what SHOULD be the case, is too often not.  I have been through a few things. But, I have always, in all circumstances, even in my cancer care - - NO!  Especially in my cancer care - - recognized my privilege.  I had access to melanoma specialists across the nation and beyond.  I had the money and support system that allowed me to travel for my care.  I had attained an education that allowed me to render the incomprehensible understandable.  So many in our great country have none of that, and very often that lack is directly correlated to the color of their skin.  The more melanin, the greater chance that their children have inadequate educational opportunities.  Those with brown skin suffer far greater health disparities - lack of access to medical care, lack of insurance, lack of being taken seriously when they do go to the doctor with complaints of illness, lack of outreach and help with basic needs that promote health like good nutrition, help with addiction, and mental health issues - than other groups.  Black and brown communities have almost no care for the silent killers of hypertension, obesity and diabetes.  Yet, those same folks work in jobs of greatest risk - for injury, for minimal wage, for less adherence to safety requirements, for long hours, for exposure to communicable disease.  In fact, the coronavirus pandemic has laid bare these inequities.  As of the first week of May, more than 80,000 people had died in the US due to COVID.  Of the nearly 65,000 deaths due to the virus for which race and ethnicity data was noted in the 39 states that compile such information, 17,155 African Americans had lost their lives to COVID-19.  Put another way, though African Americans make up only 13% of the population in those states, they make up 27% of the deaths.  When you flip those numbers, whites make up 62% of the population in those areas, but only 49% of the deaths.  In Albany Georgia, African Americans make up 90% of the deaths from COVID-19.  Why?  Because of this:

Those injustices, disproportionately meted out due to the greater content of melanin in your skin, should be enough, right?  But, like the graph above, they are only the tip of the iceberg.  Young men have died, their names making news banners yet again, at the hands of white men, simply because they were black.  They were all unarmed.  They were not committing any crimes.  They are dead.

Trayvon Martin                                 Darrell Cabey
Ahmaud Arbrey                                Barry Allen
James Ramseur                                 Troy Canty
Emmett Till
This is NOT an all inclusive list.

Police in this country are under paid and under appreciated.  Their jobs are dangerous and we all need their presence.  However, there are those among them who are not serving the public nor their fellow officers in good stead.  Racism, overt and perhaps that which even they leave unrecognized, guides their actions.  Black men die at the hands of these officers.  Police officers, Chiefs, Mayors, leaders of all stripes, and us - YES!  You and I!!! - must lead the way in removing these individuals along with the attitudes and prejudices that sustain them from our police forces so that ALL people of this nation attain the respect and protection they deserve.  The names that follow are black men who were shot and killed in recent years by police in this country.  Almost all were completely unarmed.  Many were already cuffed or had their hands in the air.  Police were on the scene due to reasons as various as a stalled car or because they - those who were soon to become victims of a police shooting - called for help due to domestic violence inflicted upon them.  Some were demonstrating clear signs of mental illness and erratic behavior while posing NO imminent threat.  Many had provided military service to our country.  Some of the names are familiar.  Far too many are not.

Sean Reed    Steven Taylor    Ariane McCree    Terrance Franklin 
Miles Hall    William Green     Samuel Mallard    Kwame Jones
Tamir Rice    Botham Jean    E J Bradford    Michael Brown
Michael Dean    Jamee Johnson    Darius Tarver    De'von Bailey
Christopher Whitfield     JaQuarnion Slaton    Antwon Rose
Stephon Clark    Yassin Mohamed    Fairan Berke 
Anthony Hill    Eric Logan    Jamarion Robinson    Gregory Hill
Ryan Twyman    Brandon Webber     Jimmy Atchinson    Willie McCoy
Walter Scott    D'ettric Griffin    Jemel Roberson     DeAndre Ballard
Rumain Brisbon    Anthony Smith    Robert White    Remarley Graham
Wendell Allen    Kendrec McDade     Larry Jackson    Jonathan Ferrell
Jordan Baker     Victor White    Dontre Hamilton    John Crawford
Ezell Ford     Dante Parker    Kajiene Powell    Laquan McDonald
Akai Gurley    Jerame Reid    Charly Keunang     Tony Robinson 
Walter Scott    Brendon Glenn    Samuel DuBose    Christian Taylor
Jamar Clark    Danny Thomas    DeJuan Gillory    Patrick Harmon 
Jonathan Hart     Maurice Granton    Julius Johnson    Mario Woods
Quintonio LeGrier    Gregory Gann     Akiel Denkins    Alton Sterling
Philando Castile    Terence Sterling    Keith Scott
Alfred Olango    Jordan Edwards     Stephon Clark    Michael Dean

This is not a complete list.           

Then there are those who died, while under arrest.  For crimes they may - or may NOT - have committed.  Died - while under arrest - under police PROTECTION.

Eric Garner and Freddie Gray readily come to mind.  Now, George Floyd has joined their ranks.
THIS is NOT a complete list.

Life while being black and brown does not have to be this way.  But it WILL continue in this manner until we - we privileged white people - we in the unaffected majority - make it otherwise.

Are you willing to recognize the problem?  Because that is where we must start.  Are you willing to do something about it?

For all the lives lost, for all the families who have buried dear ones for no other reason than their skin had more melanin than mine, I send you this -

- with the promise, that I see you.  I hear you.  I ache for you.  I am sorry.  I will do what I can to make your lives, and therefore the lives of everyone in this country - better.  ~ love, les