Why doesn't immunotherapy work for all melanoma patients?

WHY?????  And what should we do when it fails?  Dismaying questions with no clear answers, right?  But, researchers are working on them!

First - what to do when immunotherapy fails?

What to Do When Anti-PD-1 Therapy Fails in Patients With Melanoma.  Mooradian, Sullivan.  Oncology, April 2019.

Monotherapy with immune checkpoint inhibitors, specifically those targeting programmed death 1 (PD-1), has revolutionized the treatment of metastatic melanoma: approximately 40% of patients achieve a partial or complete response, many of which are durable. However, a subset of patients who initially respond to therapy will progress, leaving the majority of patients in need of an effective second-line approach. While some standard therapies exist, there has been robust interest in utilizing targeted immunotherapy combinations in this population to overcome primary or acquired resistance. Other approaches include treatment with anti-PD-1 agents beyond progression; targeting oligometastatic disease with surgery, radiation, and/or intratumor injections; and the use of other approved systemic therapies. This review summarizes the current available treatment strategies for patients with advanced melanoma when PD-1-directed therapy is not enough.

You should be able to get the entire article via this link: 
https://www.ncbi.nlm.nih.gov/pubmed/30990567

Note:  We already know that combining ipi with anti-PD-1 provides improved response rates as compared to anti-PD-1 as monotherapy, though for some, even that is not enough.  Here is a primer of basic melanoma treatments I put together that covers some of the treatments described above:
Melanoma Intel: A primer for current standard of care and treatment options

But, back to the first question ~ as Fierce Biotech put it in their article linked here:  What causes immuno-oncology drug resistance? 2 research teams uncover clues! 

The article notes: 

Checkpoint-inhibiting drugs have revolutionized the treatment of melanoma and other cancers by freeing up the immune system to attack tumors. But the medicines don’t work for as many as half of patients, even when they’re combined with other cancer treatments.

Now, two separate research groups have uncovered different mechanisms of immuno-oncology drug resistance. One involves the gut microbiome, while the other is related to vesicles that are produced by cancer cells.

First, a worldwide consortium of 40 scientists led by Sanford Burnham Prebys released a study demonstrating that the gut microbiome orchestrates the immune system’s response to cancer. They published their observations in the journal Nature Communications.  The Sanford Burnham Prebys-led team made the discovery by working with mice engineered to lack RING finger protein 5 (RNF5), a gene that normally works to clear damaged proteins from cells. These mice mounted a strong immune response to melanoma, so the researchers used bioinformatics technology to identify 11 bacterial strains that were plentiful in the animals’ guts. They then transferred the bacteria to normal mice and found it also induced a strong immune response to melanoma in those animals.  The researchers mapped out the immune components that were active in the gut, and they discovered that a signaling pathway called the unfolded protein response (UPR) was reduced when immune cells were activated. Then they studied tumor samples from people who had received checkpoint inhibitors, and they found reduced UPR expression correlated with a good response to treatment. 

The findings “identify a collection of bacterial strains that could turn on anti-tumor immunity and biomarkers that could be used to stratify people with melanoma for treatment with select checkpoint inhibitors," said senior author and Sanford Burnham Prebys professor Ze'ev Ronai, Ph.D...

The second study, from a team at the University of California, San Francisco (UCSF), focused on the protein PD-L1, the target of some checkpoint-inhibiting drugs. Normally, checkpoint inhibitors work by recognizing PD-L1 on the surface of cancer cells and then interfering either with it or the related protein PD-1. The UCSF researchers discovered that in some patients, PD-L1 travels throughout the body, inhibiting immune cells before they can reach the cancer.

In those patients, the PD-L1 ends up in exosomes, which are vesicles that come from cancer cells and travel in the bloodstream to the lymph nodes, the UCSF team discovered. While there, they “disarm” the immune cells, so they’re unable to launch an attack against the cancer. They published their findings in the journal Cell.  The prevailing view of why patients sometimes don’t respond to PD-L1 inhibitors is that their cancers are not making enough of the protein. But the UCSF researchers showed "the protein was in fact being made at some point, and that it wasn't being degraded,” senior author Robert Blelloch, M.D,. Ph.D.... said... “That's when we looked at exosomes and found the missing PD-L1."  In a second experiment, the UCSF team used the gene-editing technology CRISPR to delete two genes necessary for exosome production from cancer cells. Mice that received those cells had more activated immune cells in their lymph nodes than did animals that got unedited cancer cells.  They then treated a mouse model of colorectal cancer with a combination of a PD-L1 inhibitor and a drug that prevents exosomes from forming. Those mice survived longer than animals treated with either drug alone did.  Blelloch’s team plans to conduct further studies, with the ultimate goal of developing a “tumor cell vaccine” to help patients who don’t currently respond to checkpoint inhibitors.

SO...two very different things are addressed within this article....
1.  The cooties in our gut make a difference.  I've been writing about this for some time.   Here is a recent report with links to many more within:  DECREASED progression free survival in melanoma patients treated with antibiotics prior to or at start of immunotherapy!!!!    Side note:  Additional studies show that you have to consume the real deal.  Probiotics out of a bottle won't do the trick.  In fact, attaining your cooties that way may actually DECREASE your response to immunotherapy.
2.  The whole PD-L1 positive vs NOT positive thing!  We have long known that having PD-L1 positive tumors does not guarantee a response.  AND... folks with tumors NEGATIVE for PD-L1 can still sometimes gain one!  Here are a bunch of reports addressing the PD-L1 conundrum!

There is also this report on the same research in the NY Times from April: Cancer’s Trick for Dodging the Immune System, where the author notes:

Cancer immunotherapy drugs, which spur the body’s own immune system to attack tumors, hold great promise but still fail many patients. New research may help explain why some cancers elude the new class of therapies, and offer some clues to a solution.  The study, published on Thursday in the journal Cell, focuses on colorectal and prostate cancer. These are among the cancers that seem largely impervious to a key mechanism of immunotherapy drugs.  The drugs block a signal that tumors send to stymie the immune system. That signal gets sent via a particular molecule that is found on the surface of some tumor cells.  The trouble is that the molecule, called PD-L1, does not appear on the surface of all tumors, and in those cases, the drugs have trouble interfering with the signal sent by the cancer.  The new study is part of a growing body of research that suggests that even when tumors don’t have this PD-L1 molecule on their surfaces, they are still using the molecule to trick the immune system.  Instead of appearing on the surface, the molecule is released by the tumor into the body, where it travels to immune system hubs, the lymph nodes, and tricks the cells that congregate there.

“They inhibit the activation of immune cells remotely,” said Dr. Robert Blelloch, associate chairman of the department of urology at the University of California, San Francisco, and a senior author of the new paper.  The U.C.S.F. scientists discovered that they could cure a mouse of prostate cancer if they removed the PD-L1 that was leaving the tumor and traveling to the lymph nodes to trick the immune system. When that happened, the immune system attacked the cancer effectively.

Furthermore, the immune system of the same mouse seemed able to attack a tumor later even when the drifting PD-L1 was reintroduced. This suggested to Dr. Blelloch that it might be possible to train the immune system to recognize a tumor much the way a vaccine can train an immune system to recognize a virus.  The work was done not in humans but in laboratory experiments and in mice, and it is not clear whether the results will translate in people. Dr. Ira Mellman, vice president of cancer immunology at Genentech, called the findings “a most interesting result.”  “But as with all mouse experiments, you get insight into basic mechanisms, but how it translates to the human therapeutic setting is unclear,” said Dr. Mellman. He is skeptical, he said, but plans to meet shortly with Dr. Blelloch to discuss the implications of the work.  The new research dovetails with other recent studies, including a paper published last year in the journal Nature that showed that PD-L1 molecules released from skin cancer tumors can suppress the body’s immune function.  When these bits of PD-L1 travel outside the cell, they are known as exosomal, and the discovery of their role is one of many fast-moving developments refining an area of medicine that has become among the most promising in decades.

Late last year, the Nobel Prize was awarded to two scientists — James P. Allison of the M.D. Anderson Cancer Center in Houston, and Tasuku Honjo of Kyoto University in Japan — who did groundbreaking work in immunotherapy.  An explosion of additional research is aimed not only at refining the therapies — which can have profound side effects — but also at searching for other molecules involved in the perilous dance between cancer and the immune system.  Far more study is needed. But Dr. Blelloch said the findings have him looking for ways to take the next steps into turning the discovery into a concrete therapy.  Interfering with the PD-L1 traveling to lymph nodes “can lead to a long-lasting, systemic, anti-tumor immunity,” the paper concluded.

While this research leaves us with plenty of unanswered questions...it is the first in a long while that begins to answer the PD-L1 conundrum!!!    Here's a link to a related article from Nature if you like to read all the science for yourself:  Exosomal PD-L1 Contributes to Immunosuppression and is Associated with anti-PD-1 Response  

Hopefully, more complete answers and treatment solutions will be developed SOON!!!  Hang in there, ratties! - c