PD1-positivity and PD-L1 expression

[Olga]

Tumor Infiltrating PD1-Positive Lymphocytes and the Expression of PD-L1 Predict Poor Prognosis of Soft Tissue Sarcomas
Recently, the possibility of PD1 pathway-targeted therapy has been extensively studied in various human malignant tumors. However, no previous study has investigated their potential application for soft-tissue sarcomas (STS). In this study, we evaluated the clinical impact of intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression in tumor cells in 105 cases of STS. Intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression were seen in 65% and 58% of STS, respectively. Both PD1-positivity and PD-L1 expression were significantly associated with advanced clinicopathological parameters such as higher clinical stage, presence of distant metastasis, higher histological grade, poor differentiation of tumor, and tumor necrosis. Moreover, both PD1-positivity and PD-L1 positivity were independent prognostic indicators of overall survival (OS) and event-free survival (EFS) of STS by multivariate analysis.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859621/

[jenhy168]

Does this mean that Opdivo (nivolumab) is not good to try...?

[Olga]

No. it does not. I am not sure re. clinical significance of these findings. It looks like at the later stages of the PD1-positive diseases their expression increases, so might be a better target then? We do not even know if a given ASPS patient's tumor has this positive expression.

[jenhy168]

I see, thank you Olga.

[jenhy168]

So far Opdivo (nivolumab) side effects are very minimal. I've only had one infusion so far and I've had some itching / rashes on my body.

Onco says that side effects usually start after the 2nd infusion treatment.

[D.ap]

So far Opdivo (nivolumab) side effects are very minimal. I've only had one infusion so far and I've had some itching / rashes on my body.

Onco says that side effects usually start after the 2nd infusion treatment.

Jen

Hugs..

Your next appointment is?

Are the rashes to be expected?

Love
Deb

[Bonni Hess]

Dear ASPS Community Friends,
It is with the deepest sorrow that I learned that a young teenage ASPS patient who had received PDL-1 treatment devastatingly passed away earlier this week following her very courageous and increasingly challenging three year battle with this insidious disease.
As I deeply grieve the tragic loss of another precious young Life, I also mourn the heartbreaking apparent failure of the promising new PDL-1 treatment as a possible effective treatment option for ASPS, although I know that each patient is different and may respond differently to various treatments. Hopefully at some point in time in the future, the patient's family will be willing to post information about the patient's PDL-1 treatment and the failed results, as well as information about her ASPS journey, so that other ASPS Community members can learn and benefit from the information. In the meantime, our relentless search for an effective treatment and cure must go on so that no more precious young Lives are lost to this monstrous disease.
With a heart heavy with deepest sorrow and immense anger for the tragic and devastating loss of yet another young Life to ASPS, but still holding tight to continued Hope,
Bonni

[rachelve]

I run an ASPS Facebook group and wanted to chime in on this topic and let you know that we have in fact had 3 success stories with PD-L1 therapy in our group alone, myself included. All three of the success stories include the PD-L1 inhibitor MEDI4736 as part of various clinical trials. The first ASPS patient has been on MEDI4736 for a year now and has had 56% shrinkage of her tumors overall. The second ASPS patient has been on a clinical trial with a combination of MEDI4736 and tremeluminab. The tremeluminab therapy was only for the first 4 months and then she was supposed to continue with just the MEDI4736 thereafter. Unfortunately, after the 4th month dosing, she developed severe colitis as a side effect of the tremeluminab and has had to cease treatment temporarily while she recovers. She hopes to resume the trial soon with just the MEDI4736 as scheduled. To date, however, after only 4 months of treatment, she has had 30% shrinkage of her tumors overall and her tumors have continued to shrink although she has had to cease therapy and start high dose steroids to treat her colitis. Finally, I have been part of a clinical trial at MD Anderson since June 22nd taking a combination of MEDI4736 and Mogamulizumab. Today I got the results of my 4 month scans and learned that my tumors have shrunk a total of 48% overall. My side effects have included a rash and moderate fatigue, but overall, I have found the immunotherapy drugs to be very tolerable. Feel free to let me know if you have any further questions about my treatment. While Nathalie's outcome was indeed tragic and I know her father and the rest of her family is grieving her death, I think they would agree that we should not reject immunotherapy out of hand based upon one outcome.

[Olga]

Hi there, thank you for adding this very valuable information. Was Nathalie on a different PD-L1 therapy drug? I think that there are several? Why don't you guys post here in addition to the Facebook group? Facebook format does not allow for the systematic collection of the information and discussion by the topics/patient cases, right? This info is to valuable to be lost.
I am super happy and intrigued to hear that MEDI4736 is showing the high rate of sustainable success in ASPS. As I understand from your post, the longest case of ASPS patient on it is about a year now, with no sign of the resistance developed - the response continued.

I have few questions:
- do you know of any ASPS patients initially responding to MEDI4736 and eventually developing a resistance with the disease progressing?
- do you know of any ASPS patients who did not respond to MEDI4736 (no shrinkage or stability with the disease progressing)?
- would you attribute the side effects that you are experiencing to MEDI4736 or to Mogamulizumab? I know it is probably hard to tell but what other patients who are on the clinical trials with MEDI4736 could tell, any overlap?
I will open a separate sub-forum for this new promising MEDI4736 drug so you guys can post there and may be someone else too. Thanks again.

[rachelve]

To answer your question as to why we do not post here in addition to Facebook, we are a very new group that just formed from a few ASPS patients who kept in contact regularly from the larger Sarcoma Alliance board on Facebook. I will share a link to this forum on the Facebook group wall and encourage the members to post, but it is a small group and not very active, so I am unsure if you will see many posts here in response to my message. I think many people are just more comfortable with the Facebook format these days.

Also, I do not recall exactly which drug Nathalie was on, but I know it was one of the FDA approved PD-1 inhibitors so it was either Nivolumab or pembroluzimab.

I will answer your remaining questions by copying and pasting your questions and inserting my answers.

I have few questions:
- do you know of any ASPS patients initially responding to MEDI4736 and eventually developing a resistance with the disease progressing? I only know of the 3 patients I told you about so far and none of us have developed a resistance thus far.
- do you know of any ASPS patients who did not respond to MEDI4736 (no shrinkage or stability with the disease progressing)? No. All 3 ASPS patients I know of that have taken the MEDI4736 have responded thus far. In fact, the other two patients are both treated by Dr. Razak at Prince Margaret Hospital in Toronto and he has been in touch with the sponsors of the MEDI4736 trials about starting a trial just for ASPS patients based upon these results thus far.
- would you attribute the side effects that you are experiencing to MEDI4736 or to Mogamulizumab? I know it is probably hard to tell but what other patients who are on the clinical trials with MEDI4736 could tell, any overlap? It would be hard to say, but I do believe I am the only one with a rash, so that may indicate that the rash is from the Mogamulizumab. Immunotherapy in generally has similar side effect profiles though of fatigue, rash, etc. I will say that in trials of the MEDI4736 alone the rates of grade 3/4 side effects were surprisingly low compared to other immunotherapy drugs.

Please let me know if you have any other questions.

Rachel

[Olga]

Thank you for answering. Probably this new drug is more effective than the approved ones.
I have a question about the primary tumor - is your primary (and other two patient's that are also on this drug) resected? We have noticed that usually the response to a drug is better when the primary resected, especially if it is large. I read on this subject extensively before - there are few substances that are actively emitted by the primary (or other large tumors, sometimes metastases can grow big too and start acting like a primary emitting these things). They directly produce some of these and also provide the specific signaling for the body to produce more of others. It may interfere with the body's reaction to drugs, i.e. response of the patient with the unresected primary can be different from the one without the primary. So do you have a primary intact (and other patients) and is it responding as well?
Also are there signs of the heterogeneity in response between the metastases depending on their size/location?
How to find the Facebook group.

[Bonni Hess]

Dear Rachel,
I am so very appreciative of you reaching out to the Board to share this very important and encouraging information, and so deeply grateful that some patients, including yourself, are thus far having postiive, successful, and very encouraging results from your PDL-1 treatments. My questions and comments are the same as Olga's so I will not repeat them. I would just like to strongly encourage you and the other Facebook group ASPS patients to actively participate on this Forum which is an invaluable source of shared researched and anecdotal treatment information as well as strengthening support and encouragement for all ASPS patients and their families throughout the world. Because ASPS is so extremely rare and there are so few patients,(but certainly not few enough), it is important that we all come together on a main site to share information so that it is not divided in many different locations. There is strength in numbers, and shared information is truly one of our strongest and most effective weapons in fighting this very challenging disease because we can all learn and benefit from each other's experiences.
My very best wishes are with you and the other PDL-1 ASPS patients for continued treatment success, and I will be anxiously awaiting yours, and Hopefully their, updates on this Board.
With deepest gratitude for your thoughtful sharing, and with special caring thoughts, healing wishes, and continued Hope,
Bonni Hess, mother of now 33 year old Brittany diagnosed 14+ years ago at age 19 in 2001, and currently on a Cediranib Trial with very thankfully 6+ years of sustained disease stability and dramatic shrinkage/disappearance of all of her innumerous and widely disseminated mets

[D.ap]

Tumor Infiltrating PD1-Positive Lymphocytes and the Expression of PD-L1 Predict Poor Prognosis of Soft Tissue Sarcomas
Recently, the possibility of PD1 pathway-targeted therapy has been extensively studied in various human malignant tumors. However, no previous study has investigated their potential application for soft-tissue sarcomas (STS). In this study, we evaluated the clinical impact of intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression in tumor cells in 105 cases of STS. Intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression were seen in 65% and 58% of STS, respectively. Both PD1-positivity and PD-L1 expression were significantly associated with advanced clinicopathological parameters such as higher clinical stage, presence of distant metastasis, higher histological grade, poor differentiation of tumor, and tumor necrosis. Moreover, both PD1-positivity and PD-L1 positivity were independent prognostic indicators of overall survival (OS) and event-free survival (EFS) of STS by multivariate analysis.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859621/

Hi Rachel,

My name is Debbie and our son Josh has ASPS and was dx'd in September of 2012
This post, quote , above was first presented by Olga after there were inquiries from some of our friends about the PD drugs

Does the clinical trial test for PD positive expressions with in the group?

Can you please link us to the clinical trial in Canada ? when you get a chance.

Also we have a friend who is on Opdivo from her oncologist and has been on it since July 2015 and who could benefit greatly from all of your inputs.
She has been battling alveolar soft part sarcoma since 2009 and has hundreds of un resected lung tumors. She has tried everthing from pazonib to sutent, which stabilized her for two years to IMRT for her lungs recently.

Her name is Jen

And last BUT not least thank you soo much for coming forward and posting of your experience.

We all hope to talk soon

All my love
Debbie

[rachelve]

Olga,

I will try to answer all of your questions. With regard to the primary tumors being resected, I know for sure that my primary was resected and the primary tumor of the patient on the MEDI4736 plus tremeluminab (with 30% tumor shrinkage) was also resected. I am not sure about the 3rd patient. Notably, my primary tumor did recur, which is unusual for ASPS, but when it was removed from the muscle of my abdominal wall (where my primary was located), the tumor split. The surgeon assured me that it split outside the abdomen and no cells were spilled, but the nodular pattern of growth of my abdominal recurrence is consistent with the tumor having split inside the abdominal cavity and cells spilling and seeding into the abdominal wall muscle. I will say that there does seem to be a heterogeneity of response amongst mets in all locations (lungs, liver, lymph nodes, etc. to the best of my knowledge with regard to all 3 of us. Finally, the link to our facebook group is: https://www.facebook.com/groups/ASPSSupportGroup/.

Rachel

[rachelve]

Hi Debbie,

Here is the link to the two studies the other ladies from Canada are participating in:

https://www.clinicaltrials.gov/ct2/show ... US&rank=13

https://www.clinicaltrials.gov/ct2/show ... ocs=Y#locn

Here is the link to the study I am participating in at MD Anderson:

https://www.clinicaltrials.gov/ct2/show ... US&rank=26

I was randomized to arm 3A of the dose escalation phase of the trial, so I am at the highest dose of the combination of MEDI4736 and Mogamulizumab.

With regard to testing for PD-L1 expression, it is not routinely done as part of my trial and I do not believe it is done as part of the other two trials. However, my sarcoma specialist at MD Anderson, Dr. Conley did send my tumor biopsy from my previous clinical trial in January 2015 for testing for PD-L1 expression and my tumor showed very big levels of PD-L1 expression. In fact, he said he never saw a sample stain show such a positive result. He said he would be shocked if PD-1/ PD-L1 inhibitors weren't effective for me based upon the results of this testing, so I specifically sought out a clinical trial with PD-1 / PD-L1 inhibitors. I had already heard about the one positive result with MEDI4736, so I focused on trials utilizing that drug. It was VERY difficult to get a spot in a clinical trial for these drugs, but in the end I got lucky and got a spot off the waiting list for this trial and was randomized to the MEDI4736 arm at the highest dosage.

I really can relate and empathize with your friend, Jen, I don't know exactly how many lung tumors I started out with, but it was at least 100 total, probably closer to 150 tumors, with at least 15-20 of those being over 1cm in size. I also had the abdominal recurrence that was pretty much the size of my primary tumor at 6cm x 5cm at the biggest cluster of nodules and with a couple of other clusters of nodules in the 2cm x 3cm range and a few other scattered nodules as well. Luckily I only have tumors in my lungs and abdomen. Prior to this clinical trial, I had tried Sutent, Votrient, cabozantinib, and was on a clinical trial with a combo of Affinitor and Caprelsa. Other than Sutent, which worked for about 6 months, none of these treatments worked. I'm so grateful to have finally found a treatment that works after 3 years of fighting this awful disease.

Please let me know if I can answer any other questions.