A rare pleasure…

[Swerd]

I've been retired a little longer than 1½ years. I worked for many years in cancer research, and for the last 20 years I worked for a group in the National Cancer Institute, called the Cancer Therapy Evaluation Program (CTEP). We played a major role in performing clinical trials of new experimental cancer drugs. For the most part, this involved unsuccessful efforts. For many types of cancer, treatment can be little better than mortician's work. Most patients die.

Earlier today, I was on the phone talking with a friend and neighbor who was diagnosed, over a year ago, with cholangiocarcinoma (bile duct cancer). This is a somewhat rare disease (about 2,000-3,000 new cases a year in the US). It also is rapidly lethal unless found early enough for surgery to cure it. Sometime last June, he began taking a new drug called Keytruda (also known as pembrolizumab). It's a monoclonal antibody found to be highly effective in treating lung cancer and melanoma. It hasn't been tested in clinical trials against cholangiocarcinoma*, but within 8 weeks my friend went from preparing his funeral to renewing his passport.

*Note: this drug was available to my friend because of the FDA Expanded Access policy.

In the bleak world of cancer treatment, this drug (and another similar drug called Opdivo) have been essentially out-of-the-park home runs. They have been nothing short of revolutionary.

In my last 4 years before retiring, I was one of the scientists at CTEP who worked on the more than 30 clinical trials involving these drugs. I never thought I would be able to brag about something so successful as this !!!

 

[Drunkpenguin]

Thank you!

 

[Swerd]

Keytruda and Opdivo are now approved for treating inoperable or metastatic forms of:

• Melanoma (Remember Jimmy Carter? He had advanced metastatic melanoma with multiple brain lesions, got Keytruda, and is in complete remission.)
• Non-small cell lung cancer (NSCLC)
• Head & neck squamous cell carcinoma (HNSCC)
• Adult & pediatric patients with refractory classic Hodgkin's lymphoma (cHL)
• Urothelial carcinoma (bladder cancer)
• Renal cell cancer
• Cervical cancer (if tumors are PD-L1 positive)
• Adult & pediatric patients primary mediastinal large B-cell lymphoma (PMBCL)

Other cancer types are now being tested, and I hope more can be added to this list.

 

[Out-Of-Phase]

Thank you for your dedication and hard work.

With all your success, it’s too bad you’re retired.

 

[Swerd]

Thank you for your dedication and hard work.

With all your success, it’s too bad you’re retired.

I'd like to be able to take full credit for this. I was a member of a team of people who worked at this together, both in the federal government (CTEP), and in the pharmaceutical industry (both Merck & Co. and Bristol-Myers Squibb). The FDA also played a major role in helping this process go much faster than it normally takes.

Everyone gets high-fives for this – especially the patients who thought they had terminal cancer .

 

[mtrycrafts]

I just sent this to my better half. She is in the field but not as you were.

 

[mtrycrafts]

Info already sent to in-law as it may benefit her. Many thanks.

 

[Swerd]

Info already sent to in-law as it may benefit her. Many thanks.

Because Keytruda and Opdivo allow the patient's immune system to target any cell that expresses high levels of a protein called PD-L1, there are now diagnostic tests that measure that. Usually tumor tissue is required from surgery or a biopsy.

If a tumor – any tumor – does express PD-L1, the patient may be eligible for this kind of immunotherapy treatment. If the tumor is one of those I listed in post #3, they can receive treatment right away without going through other kinds of chemotherapy. Others tumor types may require that a patient first go through conventional 1st-line chemotherapy and/or radiation before they can receive the immune therapy. This becomes a matter of medical ethics. New clinical trial results may add other tumor types to the approved list, and the entire process is presently being reviewed to simplify and speed things up. The goal is to allow this immunotherapy as 1st-line treatment for any tumor, lymphoma or leukemia that expresses PD-L1 and/or genetic mutations as follows (quoted from Wikipedia Pembrolizumab):

In May 2017, pembrolizumab received an accelerated approval from the FDA for use in any unresectable or metastatic solid tumor with DNA mismatch repair deficiencies or a microsatellite instability-high state (or, in the case of colon cancer, tumors that have progressed following chemotherapy). This approval marked the first instance in which the FDA approved marketing of a drug based only on the presence of a genetic mutation, with no limitation on the site of the cancer or the kind of tissue in which it originated. The approval was based on a clinical trial of 149 patients with microsatellite instability-high or mismatch repair deficient cancers who enrolled on one of five single-arm trials. Ninety patients had colorectal cancer, and 59 patients had one of 14 other cancer types. The objective response rate for all patients was 39.6%. Response rates were similar across all cancer types, including 36% in colorectal cancer and 46% across the other tumor types. Notably, there were 11 complete responses (CR = no evidence of disease after evaluation),with the remainder partial responses (PR = at least 50% tumor reduction after evaluation). Responses lasted for at least six months in 78% of responders. Because the clinical trial was fairly small, Merck is obligated to conduct further post-marketing studies to ensure that the results are valid.​

 

[Alex2507]

I'd like to be able to take full credit for this. I was a member of a team

Read: That's the cancer I cured single handedly during coffee break.

 

[Swerd]

Read: That's the cancer I cured single handedly during coffee break.

OK, I'm busted .

The real history of this is much more interesting and embarrassing. The molecular targets of these antibodies, proteins called PD-1 and PD-L1 (Programmed Death-1 and Programmed Death Ligand-1) were known about in the 1990s. PD-1 is a protein on the surface of T and B lymphocytes, cells that are responsible for the immune response. PD-L1 is a protein on other cells of the immune system called antigen-presenting cells and macrophages.

Certain types of immune lymphocytes, killer T cells, directly kill cells that are detected as foreign, such as cells infected by disease viruses. B cells secrete large amounts of antibodies, which are more useful to fight bacterial infections. Other types of T cells, called regulatory T cells, are responsible for both ramping up an immune response and shutting down the immune response once it's no longer needed. Together PD-1 and PD-L1 signal immune T and B cells to stop dividing and to actually die off.

In most fields of molecular biology, the ramping up mechanisms are much more interesting and sexy than the mechanisms that shut things down. Both are critically important. It's just like in Star Trek when the Self Destruct Mechanism is activated – nobody really likes those Self Destruct systems.

By the early 2000's this PD-1/PDL-1 programmed cell death signalling mechanism was recognized. The cancer research world ignored it for years until it became known that some tumor types acquired the ability to express large amounts of PD-L1 protein. They could escape an immune response by fooling the killer T cells to ignore them and die off instead of rapidly dividing, invading the tumor, and killing it. Its like, Alec Guiness (Obi Wan Kenobi in Star Wars) who fooled the Imperial Storm Troopers by saying "these are not the droids you're looking for".

It had been known for years that tumors somehow caused the immune system to be unresponsive, but no one understood how this worked. By 2008-09, it was understood that covering up a T or B cell's PD-1 protein with an antibody could block PD-1/PD-L1 signalling, and prevent this unresponsiveness. By 2014 the first positive results were reported in patients with melanoma. Clinical trials in other types of cancer soon followed.

It took the cancer world two decades to catch up with the rest of molecular biology and immunology .

 

[Alex2507]

. By 2014 the first positive results were reported in patients with melanoma.

That's note worthy, mainly because I recognize the name after living in Fla. That's all the retirees ever talk about, well, that and their gout ... j/k

Seriously, I sort of keep an eye out for skin stuff on account of those years in the sun, never mind the couple of years spent in TX. I'm glad to know there's something out there for that ... just in case this living forever thing doesn't work out, but so far, so good.

more than 30 clinical trials involving these drugs

I'm over here conducting mini seminars on the differences between stage 1, 2 and 3 trials with my various PT people and anybody else who will listen like I'm smart. I don't explain how I know either. It adds to that international man of mystery thing. People think I'm brilliant. I let them.

 

[Swerd]

And now, with perfect timing…

STOCKHOLM -- The Nobel Prize in medicine was awarded Monday to two researchers from the United States and Japan for advances in discovering how the body's immune system can fight off the scourge of cancer. The 9-million-kronor ($1.01 million) prize will be shared by James Allison of the University of Texas MD Anderson Cancer Center in Houston and Tasuku Honjo of Kyoto University.​

​

https://www.washingtonpost.com/national/health-science/nobel-prize-in-medicine-goes-to-cancer-immunotherapy-researchers/2018/10/01/e0ba8448-c55b-11e8-9b1c-a90f1daae309_story.html?utm_term=.27950b6a385c​

Allison and Honjo are the two who get credit for first discovering the complex immune checkpoint signalling pathway. It sparked a revolution in oncology and a billion-dollar market for the drugs.

 

[mtrycrafts]

I'll take your word for all those chemical interactions.

 

[Dan]

I sit on the other side of all this as an imager at a large cancer center. I spend a fair chunk of my day measuring tumors to see if they grew or shrank with the latest round of chemo. The response to these drugs is far and away the most dramatic success in cancer treatment I've seen in nearly 30 years of doing this. I guess I did my part too as many of the scans I read are part of clinical trials for evaluation of drug efficacy but usually I have no idea what drug is involved.