surgery while on Anti-PD1 trial

Yes, NCI does require a washout period.  From the inclusion criteria of one of their recent TIL trials:

"Six weeks must have elapsed from the time of any antibody therapy that could affect an anti cancer immune response, including anti-CTLA4 antibody therapy, so at the time the patient receives the preparative regimen to allow antibody levels to decline. Note: Patients who have previously received ipilimumab and have documented GI toxicity must have a colonoscopy with normal colonic biopsies."

It specifically mentions anti-CTLA-4, but safe to assume that "antibody therapy" includes anti-PD-1, too.

As far as freezing of TILs for future use, that's not 100% clear.  They don't have an offering to harvest TILs to be frozen "just in case" you decide to enter a TIL trial down the road.  However, they do freeze TILs for other reasons.  My understanding is that a small sample of the TILs to be infused are preserved for a possible subsequent retreatment (although a subsequent retreatment with TILs derived from the same source is rare).

My TIL harvest experience followed a peculiar path.  The trial I was in at NCI was to evaluate the benefit of pretreating with high-dose IL-2, so it was constructed with two arms and a crossover.  Patients were randomized 50/50 to start with either IL-2 or TIL.  The IL-2 arm received a standard HD IL-2 protocol of round of IL-2, 7-10 days off, then another round of IL-2, followed by a 6 week wait and scans, with the cycle repeated twice more or until disease progression.  If or when there was disease progression, patients were then crossed over to the TIL arm.

I was randomized to the TIL arm and within 4 days was in Bethesda for apheresis and the TIL harvest surgery to remove my original lesion (on my back).  About a week later, I got a call from my Fellow that the cells weren't growing fast enough to yield a sufficient number of TIL cells for reinfusion.  He explained that they would continue to try growing them, but that they would probably eventually "declare" and stop growing altogether.  So I was crossed over to the IL-2 arm and three days later was back in Bethesda to start the first round of IL-2.  I did the first two rounds of IL-2 and when I came back for my 6 week scans and to possibly start the next round of IL-2, it was a "bad news/good news" report.  A bone met in my shoulder had progressed to the point where they were concerned about fracture risk.  However, they had continued trying to grow my TILs (as they said they would) and they did eventually start to grow better.  But I couldn't proceed with the TILs because the fracture risk was so high with my arm that they were concerned I could easily break it (even rolling over in my sleep) and with no immune system after the preparatory chemotherapy regimen, the risk of a life-threatening infection would be too great.  So the plan was to have the bone met addressed (I had an arthroplasty of my entire proximal humerus and now have a 10 inch titantium implant there) and then cross me back over to the TIL arm.  There were some questions about crossing back over, but it all worked out.  So the TILs were frozen while I went through the arthroplasty and recovered.

After recovering from surgery enough to start TIL, we went down to NCI again to get new scans and unfortunately found several new mets (small intestine, soft tissue of my temple, and internal chest wall).  The small intestine one was a particular challenge, again because of the risk of intestinal bleeding and infection.  The other mets were ones that they hoped the TIL would treat.  So I had to have a small bowel resection – they took about 6-8 inches of my small intestine, including a tumor that was a couple of inches across.

They also decided to try growing TILs from that harvested tumor and they grew "like wildfire".  Within three weeks they had enough cells for treatment, and those were the cells I eventually received.  My original TILs are still frozen and "on file" so to speak, as are samples of the ones I received.

Hope that helps.

Yes, NCI does require a washout period.  From the inclusion criteria of one of their recent TIL trials:

"Six weeks must have elapsed from the time of any antibody therapy that could affect an anti cancer immune response, including anti-CTLA4 antibody therapy, so at the time the patient receives the preparative regimen to allow antibody levels to decline. Note: Patients who have previously received ipilimumab and have documented GI toxicity must have a colonoscopy with normal colonic biopsies."

It specifically mentions anti-CTLA-4, but safe to assume that "antibody therapy" includes anti-PD-1, too.

As far as freezing of TILs for future use, that's not 100% clear.  They don't have an offering to harvest TILs to be frozen "just in case" you decide to enter a TIL trial down the road.  However, they do freeze TILs for other reasons.  My understanding is that a small sample of the TILs to be infused are preserved for a possible subsequent retreatment (although a subsequent retreatment with TILs derived from the same source is rare).

My TIL harvest experience followed a peculiar path.  The trial I was in at NCI was to evaluate the benefit of pretreating with high-dose IL-2, so it was constructed with two arms and a crossover.  Patients were randomized 50/50 to start with either IL-2 or TIL.  The IL-2 arm received a standard HD IL-2 protocol of round of IL-2, 7-10 days off, then another round of IL-2, followed by a 6 week wait and scans, with the cycle repeated twice more or until disease progression.  If or when there was disease progression, patients were then crossed over to the TIL arm.

I was randomized to the TIL arm and within 4 days was in Bethesda for apheresis and the TIL harvest surgery to remove my original lesion (on my back).  About a week later, I got a call from my Fellow that the cells weren't growing fast enough to yield a sufficient number of TIL cells for reinfusion.  He explained that they would continue to try growing them, but that they would probably eventually "declare" and stop growing altogether.  So I was crossed over to the IL-2 arm and three days later was back in Bethesda to start the first round of IL-2.  I did the first two rounds of IL-2 and when I came back for my 6 week scans and to possibly start the next round of IL-2, it was a "bad news/good news" report.  A bone met in my shoulder had progressed to the point where they were concerned about fracture risk.  However, they had continued trying to grow my TILs (as they said they would) and they did eventually start to grow better.  But I couldn't proceed with the TILs because the fracture risk was so high with my arm that they were concerned I could easily break it (even rolling over in my sleep) and with no immune system after the preparatory chemotherapy regimen, the risk of a life-threatening infection would be too great.  So the plan was to have the bone met addressed (I had an arthroplasty of my entire proximal humerus and now have a 10 inch titantium implant there) and then cross me back over to the TIL arm.  There were some questions about crossing back over, but it all worked out.  So the TILs were frozen while I went through the arthroplasty and recovered.

After recovering from surgery enough to start TIL, we went down to NCI again to get new scans and unfortunately found several new mets (small intestine, soft tissue of my temple, and internal chest wall).  The small intestine one was a particular challenge, again because of the risk of intestinal bleeding and infection.  The other mets were ones that they hoped the TIL would treat.  So I had to have a small bowel resection – they took about 6-8 inches of my small intestine, including a tumor that was a couple of inches across.

They also decided to try growing TILs from that harvested tumor and they grew "like wildfire".  Within three weeks they had enough cells for treatment, and those were the cells I eventually received.  My original TILs are still frozen and "on file" so to speak, as are samples of the ones I received.

Hope that helps.

Like anything, that's a loaded question, but I'll try to keep it short.  Long story short, I had a good response to TIL once I finally started.  With the twists and turns I mentioned above, from the time I signed on the dotted line for the trial until the time I received my cells was about 7 months, but I was thankful to have navigated those challenges to make it to that point.  The day I received my TIL infusion, I had three known metastases:  one in the soft tissue on my temple, one in the internal chest wall (mediastinum), and at least one lymph node in my underarm.  As I mentioned, by that point I'd had two previous tumors harvested for cells, the first was the original lesion on my back, and the second was in my small intestine – the second is what we ended up being what was used for the "batch" of cells I received.  Additionally, I had the tumor in my proximal humerus that was resected and the bone replaced with a titanium implant.

Within a week of receiving the cells, the one on my temple – a lump that was visible and palpable – was visibly shrinking.  I was still at NIH recovering from the IL-2 and my wife and I both noticed it, but were almost afraid to hope (and say anything to each other) that it could actually be shrinking so quickly.  But we asked one of my doctors and he confirmed that, yes, it's possibly it could be happening that soon.  It could also have been the chemotherapy regimen, but if that was the case, the shrinking wouldn't last long.  Within six weeks, I could neither see or feel it.  My six week scans confirmed what we were seeing.  The temple, mediastinal, and node tumors were all decreasing in size.  I received the TIL in March 2011, that 6 week scan was at the end of April.  The next 6 week scan in early June showed additional decrease, not by leaps and bounds, but clinically significant.  

Unfortunately we hit a bump in the road then.  I had gone running on a treadmill at the gym a couple of times in the previous weeks and noticed someting in my left shin.  It wasn't painful, just a new sensation that didn't feel muscular, definitely bone, and I'd never suffered from shin splints before.  So at my June scan in Bethesda, I mentioned it in the interest of full disclosure.  They said to get an x-ray on the way home, before leaving for Philly from NCI.  A couple of days later, my Fellow called and basically said that they couldn't agree on if they were seeing something or nothing, it was minor enough, but recommended I have an MRI to get a better look.  Rather than have it at my home hospital (Fox Chase Cancer Center here in Philly – with trials at NCI, it very much works like a partnership between the home/referring hospital and NCI), it was just easier to make a day trip out of it and go back to Bethesday (3 hours one way) for the MRI – no need to deal with insurance or coordinate having it scheduled and then the images transferred to NCI.  So a few more days and they confirmed that it looked like two small bone mets in my left proximal tibia.  Standard monitoring for melanoma is a CT of chest, abdomen, and pelvis (along with an annual brain MRI), so they never even looked below my knees – I don't have any ill feelings, that's just the way it works.  And now my standard monitoring is a full-body, head-to-toe PET/CT.  So even though it's highly likely these new bone mets in my tibia had been there since well before I received my cells, for purposes of the trial monitoring, I was considered to have "progressive disease".

We scheduled radiation therapy for the bone mets and also have a full restage via PET/CT back at Fox Chase.  The PET/CT could no longer even see the temple or mediastinal tumors, neither physically or metabolically, and the node was decreasing in metabolic "brightness".  My surgical oncologist at Fox Chase, who had helped us find and connect with NCI the year prior, suggested we go ahead and remove the node and the cluster of nodes around it.  It was only left in as part of the trial to measure response, and since I was officially "progressive", there was no need to leave it in.  He removed six nodes – four were clean, one should minimal involvement, and the one that had been the biggest concern was fairly large, but also consisted of a large portion of necrotic (dead scar) tissue with the assumption that the TIL was doing its thing there, too.

So technically, I had a good but short-lived response to TIL before disease progression, but the actual truth is that all of the treated tumors had (or were in the process of) experienced a complete response to TIL.  To this day, I've had no recurrence in the nodes, temple, or chest wall.

I have had subsequent mets, others in the leg bones soon after finding those first ones, but no new ones in nearly three years.  I've also had a slow growing lung met that's responded to radiation along with a lone brain met that was surgically removed and followed up with SRS/CyberKnife, going on 15 months without a recurrence (next brain MRI in two weeks).  I also had Yervoy/ipi a few months after the craniotomy.  So everything since the TIL has been slow-growing and treatable so far.

All in all, I consider myself a responder to TIL combined with a thoughtful approach to navigating through subsequent issues with a good team of doctors.

I hope that helps.

As far as biomarkers, I don't know if I follow your question completely, but there were no tests prior to being randomized to determine if IL-2 or TIL would be a better option.  It was a blind randomization, with the caveat that no matter which arm I started in, I'd have the ability to move to the other arm if needed.  Given the documented response rates, I certainly wanted to try TIL first, but even if I'd been randomized to IL-2,. I knew I'd eventually get TIL if the IL-2 didn't work.

Joe

Like anything, that's a loaded question, but I'll try to keep it short.  Long story short, I had a good response to TIL once I finally started.  With the twists and turns I mentioned above, from the time I signed on the dotted line for the trial until the time I received my cells was about 7 months, but I was thankful to have navigated those challenges to make it to that point.  The day I received my TIL infusion, I had three known metastases:  one in the soft tissue on my temple, one in the internal chest wall (mediastinum), and at least one lymph node in my underarm.  As I mentioned, by that point I'd had two previous tumors harvested for cells, the first was the original lesion on my back, and the second was in my small intestine – the second is what we ended up being what was used for the "batch" of cells I received.  Additionally, I had the tumor in my proximal humerus that was resected and the bone replaced with a titanium implant.

Within a week of receiving the cells, the one on my temple – a lump that was visible and palpable – was visibly shrinking.  I was still at NIH recovering from the IL-2 and my wife and I both noticed it, but were almost afraid to hope (and say anything to each other) that it could actually be shrinking so quickly.  But we asked one of my doctors and he confirmed that, yes, it's possibly it could be happening that soon.  It could also have been the chemotherapy regimen, but if that was the case, the shrinking wouldn't last long.  Within six weeks, I could neither see or feel it.  My six week scans confirmed what we were seeing.  The temple, mediastinal, and node tumors were all decreasing in size.  I received the TIL in March 2011, that 6 week scan was at the end of April.  The next 6 week scan in early June showed additional decrease, not by leaps and bounds, but clinically significant.  

Unfortunately we hit a bump in the road then.  I had gone running on a treadmill at the gym a couple of times in the previous weeks and noticed someting in my left shin.  It wasn't painful, just a new sensation that didn't feel muscular, definitely bone, and I'd never suffered from shin splints before.  So at my June scan in Bethesda, I mentioned it in the interest of full disclosure.  They said to get an x-ray on the way home, before leaving for Philly from NCI.  A couple of days later, my Fellow called and basically said that they couldn't agree on if they were seeing something or nothing, it was minor enough, but recommended I have an MRI to get a better look.  Rather than have it at my home hospital (Fox Chase Cancer Center here in Philly – with trials at NCI, it very much works like a partnership between the home/referring hospital and NCI), it was just easier to make a day trip out of it and go back to Bethesday (3 hours one way) for the MRI – no need to deal with insurance or coordinate having it scheduled and then the images transferred to NCI.  So a few more days and they confirmed that it looked like two small bone mets in my left proximal tibia.  Standard monitoring for melanoma is a CT of chest, abdomen, and pelvis (along with an annual brain MRI), so they never even looked below my knees – I don't have any ill feelings, that's just the way it works.  And now my standard monitoring is a full-body, head-to-toe PET/CT.  So even though it's highly likely these new bone mets in my tibia had been there since well before I received my cells, for purposes of the trial monitoring, I was considered to have "progressive disease".

We scheduled radiation therapy for the bone mets and also have a full restage via PET/CT back at Fox Chase.  The PET/CT could no longer even see the temple or mediastinal tumors, neither physically or metabolically, and the node was decreasing in metabolic "brightness".  My surgical oncologist at Fox Chase, who had helped us find and connect with NCI the year prior, suggested we go ahead and remove the node and the cluster of nodes around it.  It was only left in as part of the trial to measure response, and since I was officially "progressive", there was no need to leave it in.  He removed six nodes – four were clean, one should minimal involvement, and the one that had been the biggest concern was fairly large, but also consisted of a large portion of necrotic (dead scar) tissue with the assumption that the TIL was doing its thing there, too.

So technically, I had a good but short-lived response to TIL before disease progression, but the actual truth is that all of the treated tumors had (or were in the process of) experienced a complete response to TIL.  To this day, I've had no recurrence in the nodes, temple, or chest wall.

I have had subsequent mets, others in the leg bones soon after finding those first ones, but no new ones in nearly three years.  I've also had a slow growing lung met that's responded to radiation along with a lone brain met that was surgically removed and followed up with SRS/CyberKnife, going on 15 months without a recurrence (next brain MRI in two weeks).  I also had Yervoy/ipi a few months after the craniotomy.  So everything since the TIL has been slow-growing and treatable so far.

All in all, I consider myself a responder to TIL combined with a thoughtful approach to navigating through subsequent issues with a good team of doctors.

I hope that helps.

As far as biomarkers, I don't know if I follow your question completely, but there were no tests prior to being randomized to determine if IL-2 or TIL would be a better option.  It was a blind randomization, with the caveat that no matter which arm I started in, I'd have the ability to move to the other arm if needed.  Given the documented response rates, I certainly wanted to try TIL first, but even if I'd been randomized to IL-2,. I knew I'd eventually get TIL if the IL-2 didn't work.

Joe

Like anything, that's a loaded question, but I'll try to keep it short.  Long story short, I had a good response to TIL once I finally started.  With the twists and turns I mentioned above, from the time I signed on the dotted line for the trial until the time I received my cells was about 7 months, but I was thankful to have navigated those challenges to make it to that point.  The day I received my TIL infusion, I had three known metastases:  one in the soft tissue on my temple, one in the internal chest wall (mediastinum), and at least one lymph node in my underarm.  As I mentioned, by that point I'd had two previous tumors harvested for cells, the first was the original lesion on my back, and the second was in my small intestine – the second is what we ended up being what was used for the "batch" of cells I received.  Additionally, I had the tumor in my proximal humerus that was resected and the bone replaced with a titanium implant.

Within a week of receiving the cells, the one on my temple – a lump that was visible and palpable – was visibly shrinking.  I was still at NIH recovering from the IL-2 and my wife and I both noticed it, but were almost afraid to hope (and say anything to each other) that it could actually be shrinking so quickly.  But we asked one of my doctors and he confirmed that, yes, it's possibly it could be happening that soon.  It could also have been the chemotherapy regimen, but if that was the case, the shrinking wouldn't last long.  Within six weeks, I could neither see or feel it.  My six week scans confirmed what we were seeing.  The temple, mediastinal, and node tumors were all decreasing in size.  I received the TIL in March 2011, that 6 week scan was at the end of April.  The next 6 week scan in early June showed additional decrease, not by leaps and bounds, but clinically significant.  

Unfortunately we hit a bump in the road then.  I had gone running on a treadmill at the gym a couple of times in the previous weeks and noticed someting in my left shin.  It wasn't painful, just a new sensation that didn't feel muscular, definitely bone, and I'd never suffered from shin splints before.  So at my June scan in Bethesda, I mentioned it in the interest of full disclosure.  They said to get an x-ray on the way home, before leaving for Philly from NCI.  A couple of days later, my Fellow called and basically said that they couldn't agree on if they were seeing something or nothing, it was minor enough, but recommended I have an MRI to get a better look.  Rather than have it at my home hospital (Fox Chase Cancer Center here in Philly – with trials at NCI, it very much works like a partnership between the home/referring hospital and NCI), it was just easier to make a day trip out of it and go back to Bethesday (3 hours one way) for the MRI – no need to deal with insurance or coordinate having it scheduled and then the images transferred to NCI.  So a few more days and they confirmed that it looked like two small bone mets in my left proximal tibia.  Standard monitoring for melanoma is a CT of chest, abdomen, and pelvis (along with an annual brain MRI), so they never even looked below my knees – I don't have any ill feelings, that's just the way it works.  And now my standard monitoring is a full-body, head-to-toe PET/CT.  So even though it's highly likely these new bone mets in my tibia had been there since well before I received my cells, for purposes of the trial monitoring, I was considered to have "progressive disease".

We scheduled radiation therapy for the bone mets and also have a full restage via PET/CT back at Fox Chase.  The PET/CT could no longer even see the temple or mediastinal tumors, neither physically or metabolically, and the node was decreasing in metabolic "brightness".  My surgical oncologist at Fox Chase, who had helped us find and connect with NCI the year prior, suggested we go ahead and remove the node and the cluster of nodes around it.  It was only left in as part of the trial to measure response, and since I was officially "progressive", there was no need to leave it in.  He removed six nodes – four were clean, one should minimal involvement, and the one that had been the biggest concern was fairly large, but also consisted of a large portion of necrotic (dead scar) tissue with the assumption that the TIL was doing its thing there, too.

So technically, I had a good but short-lived response to TIL before disease progression, but the actual truth is that all of the treated tumors had (or were in the process of) experienced a complete response to TIL.  To this day, I've had no recurrence in the nodes, temple, or chest wall.

I have had subsequent mets, others in the leg bones soon after finding those first ones, but no new ones in nearly three years.  I've also had a slow growing lung met that's responded to radiation along with a lone brain met that was surgically removed and followed up with SRS/CyberKnife, going on 15 months without a recurrence (next brain MRI in two weeks).  I also had Yervoy/ipi a few months after the craniotomy.  So everything since the TIL has been slow-growing and treatable so far.

All in all, I consider myself a responder to TIL combined with a thoughtful approach to navigating through subsequent issues with a good team of doctors.

I hope that helps.

As far as biomarkers, I don't know if I follow your question completely, but there were no tests prior to being randomized to determine if IL-2 or TIL would be a better option.  It was a blind randomization, with the caveat that no matter which arm I started in, I'd have the ability to move to the other arm if needed.  Given the documented response rates, I certainly wanted to try TIL first, but even if I'd been randomized to IL-2,. I knew I'd eventually get TIL if the IL-2 didn't work.

Joe

Yes, NCI does require a washout period.  From the inclusion criteria of one of their recent TIL trials:

"Six weeks must have elapsed from the time of any antibody therapy that could affect an anti cancer immune response, including anti-CTLA4 antibody therapy, so at the time the patient receives the preparative regimen to allow antibody levels to decline. Note: Patients who have previously received ipilimumab and have documented GI toxicity must have a colonoscopy with normal colonic biopsies."

It specifically mentions anti-CTLA-4, but safe to assume that "antibody therapy" includes anti-PD-1, too.

As far as freezing of TILs for future use, that's not 100% clear.  They don't have an offering to harvest TILs to be frozen "just in case" you decide to enter a TIL trial down the road.  However, they do freeze TILs for other reasons.  My understanding is that a small sample of the TILs to be infused are preserved for a possible subsequent retreatment (although a subsequent retreatment with TILs derived from the same source is rare).

My TIL harvest experience followed a peculiar path.  The trial I was in at NCI was to evaluate the benefit of pretreating with high-dose IL-2, so it was constructed with two arms and a crossover.  Patients were randomized 50/50 to start with either IL-2 or TIL.  The IL-2 arm received a standard HD IL-2 protocol of round of IL-2, 7-10 days off, then another round of IL-2, followed by a 6 week wait and scans, with the cycle repeated twice more or until disease progression.  If or when there was disease progression, patients were then crossed over to the TIL arm.

I was randomized to the TIL arm and within 4 days was in Bethesda for apheresis and the TIL harvest surgery to remove my original lesion (on my back).  About a week later, I got a call from my Fellow that the cells weren't growing fast enough to yield a sufficient number of TIL cells for reinfusion.  He explained that they would continue to try growing them, but that they would probably eventually "declare" and stop growing altogether.  So I was crossed over to the IL-2 arm and three days later was back in Bethesda to start the first round of IL-2.  I did the first two rounds of IL-2 and when I came back for my 6 week scans and to possibly start the next round of IL-2, it was a "bad news/good news" report.  A bone met in my shoulder had progressed to the point where they were concerned about fracture risk.  However, they had continued trying to grow my TILs (as they said they would) and they did eventually start to grow better.  But I couldn't proceed with the TILs because the fracture risk was so high with my arm that they were concerned I could easily break it (even rolling over in my sleep) and with no immune system after the preparatory chemotherapy regimen, the risk of a life-threatening infection would be too great.  So the plan was to have the bone met addressed (I had an arthroplasty of my entire proximal humerus and now have a 10 inch titantium implant there) and then cross me back over to the TIL arm.  There were some questions about crossing back over, but it all worked out.  So the TILs were frozen while I went through the arthroplasty and recovered.

After recovering from surgery enough to start TIL, we went down to NCI again to get new scans and unfortunately found several new mets (small intestine, soft tissue of my temple, and internal chest wall).  The small intestine one was a particular challenge, again because of the risk of intestinal bleeding and infection.  The other mets were ones that they hoped the TIL would treat.  So I had to have a small bowel resection – they took about 6-8 inches of my small intestine, including a tumor that was a couple of inches across.

They also decided to try growing TILs from that harvested tumor and they grew "like wildfire".  Within three weeks they had enough cells for treatment, and those were the cells I eventually received.  My original TILs are still frozen and "on file" so to speak, as are samples of the ones I received.

Hope that helps.