Immunotherapy for Melanoma, Kidney & Lung Cancers
Hotel Intercontinental Chicago | Oct. 26, 2014
8:30 a.m. – 3 p.m.
This conference is important! If you have read much of this blog, you know that I am alive because I had the chance to enter a HighDose Interleukin treatment ten years ago. Cost is $25, including lunch.
This is a unique opportunity to hear the “rock stars” of immunotherapy–not just for kidney cancer patients, so share!
WelcomeDr. Howard (Jack) West, Swedish Cancer Institute/President of GRACE
Wendy K.D. Selig, President & CEO of Melanoma Research Alliance
What is Immunotherapy & Its Mechanisms of Action?
A History of Immunotherapy in Cancer
How Immunotherapy is Administered
TBD Q&A – Drs. Pardoll, Hellman and Gajewski; moderated by Dr. West
|10:40 a.m. Managing Immunotherapy Side Effects
Marianne J. Davis, NP, Yale Cancer Center
The Patient Perspective
Rusty Cline, Stage IV Melanoma Patient
Why is Immunotherapy More Effective in Some Cancers Than Others?
Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center
Q&A – Ms. Davis, Mr. Cline, Dr. Wolchok; moderated by Dr. West
Attendees pick up boxed lunches & proceed to breakouts
|12:15 – 1:20 p.m.
Dr. Suzanne Topalian, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Q&A moderated by Dr. Louise M. Perkins, Melanoma Research Alliance
Dr. Sumanta K. Pal, City of Hope Cancer Center
Q&A moderated by Marianne J. Davies, NP
Dr. Matthew D. Hellman
Q&A moderated by Dr. Howard (Jack) West
|1:20 p.m. Break|
Can We Identify Which Patients Will Benefit Most from Immunotherapy?
Dr. Sumanta Pal
What is the Ideal Setting for Immunotherapy?
Dr. Suzanne L. Topalian
New Endpoints for New Treatment Strategies: Redefining Success and Failure in Immunotherapy Trials
Dr. Jedd D. Wolchok
Q&A – Drs. Harshman, Wolchok; moderated by Dr. Perkins
Dr. Howard (Jack) West
How Does the Pathology Report Help Direct my Treatment Options?
Lecture by Dr. Daniel Luthringer of Cedars Sinai Medical Center of Los Angeles at Kidney Cancer Association meeting December 2013. https://www.youtube.com/watch?v=-6emPs-mc1E (Follow via YouTube)
I have transcribed the lecture edited for readability, included the slides, to make it easier to follow. If you have not seen your own pathology, GET THAT REPORT now. Important to read!
A terrific introduction by Dr. Robert Figlin reminds us of the work of those people we never meet, but who care for us. “One of the people behind the scenes is the pathologist at this and other institutions. Often times the pathologist is in a different part of the hospital evaluating tissue, and helping the clinician figure out what the tissue looks like. It’s become, as Hyung (Dr. Kim) mentioned, time to start to think about personalized approaches to kidney cancer, and the relationship between the pathologist, the surgeon, and the clinician becomes ever more important. Dr. Daniel Luthringer is Professor of Pathology and Section Chief of the Genitourinary Pathology. He will talk to us about how the pathology report and how what he does– is important to then what we decide how to go forward with treatment.”
Dr. Luthringer begins:
“Thank you, Bob, for this introduction and the ability to speak at this conference. I am the guy behind the scenes, at least at this institution responsible for doing the histologic/microscopic analysis of genitourinary malignancies, primarily renal cell carcinomas. (RCC)
1 There are really two main categories of specimens we receive, samples from the real tumor itself, which can either be biopsies or resections, as Dr. Kim alluded to, or samples from a metastatic site, a recurrence or a metastatic site. The most common specimens that we see are nephrectomies, resections of the tumor, andeither partial nephrectomy or complete nephrectomy.
2 These are examples. A partial nephrectomy, as per Dr. Kim, are smaller resections or partial resections of the entire tumor.They include a bit of nephric fat and a little bit of the perinephretic fat as well. The goal is to get the entire tumor out, with a negative margin of resection. With tumors that are bigger generally, or infiltrative, we tend to get the entire kidney. This is an example of a nephrectomy with perinephric fat, the sinus fat, drainage area down here, maybe an adrenal gland up top and this would be an example of tumor that is completely resected.
Occasionally we will get tumors from metastatic sites or—unusually from the primary tumor—and will get a core biopsy, which is really a small smaller sample of the tumor mass. Usually it is about a millimeter or two in diameter; it’s a core, maybe up to several millimeters up to a centimeter in length. Generally, it is just a small sample of a much larger tumor .
3 A bit about the specimen handling: within a few minutes of having the tissue removed, it comes to the pathology lab. We do some initial assessment on it. We have work stations where they will come and the pathology team will assess it. Assume it is a nephrology specimen. We look at it and measure it, cut it open, procure some of the tissue. If there is some tissue that needs to be taken fresh, potentially for a biobank to be stored away, or if some tissue needs to be taken for immediate diagnosis or margins or something like that, we will do that.
If you’re enrolled in a study where there some fresh tissue is needed, sent to a particular institution or a reference laboratory for an analysis, we will procure that as well and make arrangements to send it off on an immediate basis. At that point we do photography, tissue fixation and over the next few hours we will dissect the specimen, will analyze it, do a lot important evaluation with our eyes and ears, whatever it takes. Then we will take what are called representative sections of that tumor or specimen, put them. We put them into these little capsules called cassettes and then we process them overnight in these tissue processors. These are pretty standard from institution to institution.
3a The next morning the tissue is taken out of the processors and is manually placed in these other tissue cassettes which are filled with paraffin wax essentially. They are embedded into these wax molds, and then the blocks. Then very thin sections of 4 to 5 microns are cut with these special microtomes and they are picked up on the glass slides. They are again processed, stained, and cover slipped. Ultimately we get a sample of glass slides from that tumor that has been removed. On an average partial or complete nephrectomy, we will go anywhere from 5-10 paraffin blocks, equating to 5 -10 glass slides.
This takes about a day or two to complete this. Then the initial slides are delivered to the pathologist, who will begin the process of microscopic analysis. He uses obviously his microscope and whatever tools he needs.
He’ll be looking at those sections from the slides, and it will usually be the sections from the kidney, maybe some lymph nodes, margins, adrenal glands, things that were provided by the surgical resection. The whole process usually takes 2-3 days to complete. There is a bit of a time lag, due to the technical processing involved.
4a The Elements of the Report. Once we generate the report, and it becomes available, there are really three categories of information that are really relevant– not just the diagnosis, but the future care of the patient. The first is the diagnosis. What is the diagnosis? Is it really renal cell carcinoma or is it some other unusual type of renal cell cancer? I will talk more about that. Then: aspects related to cancer stage–tumor size, local infiltration. Has it metastasized or spread? Last, the other features that Dr. Kim alluded to in his talk—resection margins, grade, vascular invasions. We will talk to about these just briefly.
4bThe first aspect is diagnosis. The important thing to remember, and \I think everyone in the room is a little bit beyond this, but remember that at the initial phase, tumors are resected and often times it is not know if it is a RCC. Often times it isn’t even know if it is a neoplasm at all. Not all tumor masses are neoplastic or malignancies.
5 Examples of non-tumor masses would be like cysts, a lot of cysts. A lot like this or areas where the collecting system is dilated called hydronephrosis or multiple cysts can present or look just like a RCC. They are resected as if they were RCCs. But in fact they are not—they are benign
There are other types of tumors besides kRCCs. Angiomylipomas are a very common tumor. They could be very big like this one. Here’s a kidney. Here’s a big one. They could be multiple. Here’d two. They could be small one or 2 cm like this, but they all look like fatty tumors, but not all RCCs. Different types of tumor like fibroma or oncocytoma can be very big and aggressive-looking, but in fact, they’re not malignant at all.
6 There are other types of malignancies, true malignancies of the kidney which are not real carcinomas. Urothelial tumors, those that are derived from the lining of the kidney that can extend into the kidney, be derived of the kidney. These are examples of some of these here. They were resected, thinking that these are probably RCCs, but in fact they turned to be urothelial, not RCCs.
Different types of tumors like sarcoma can be derived of the kidney or around the kidney. Other types of tumors can metastasize to the kidney or near the kidney. Adrenal tumors, lymphomas—there is a whole host of malignancies which can mimic RCC.
7 What were really talking about today here obviously is renal cell carcinomas which represent probably 90% of more of all true malignancies of the kidney. These are the tumors which are derived from the renal tubular epithelian cells, those little ducts that line the epithelium of the kidney. The diagnosis of RCC really is contingent upon microscopic analysis. You can’t make the diagnosis any other way.
The pathologist needs to look at the gross, take a section, look under the microscopic, and then there’s a spectrum, a range of features that will ensure the diagnosis or put it into a diagnostic category of RCC. Sometimes is not so simple. We need special testing–the use of antibodies, immunohistochemical studies or even as Dr. Young Kim alluded to, sometimes we need to refer to some molecular analysis to put it into a diagnostic category of RCC.
7a Once we’ve done that, the next phrase is to determine the subtype. There are many different subtypes of RCCs really based primarily on the appearance of the tumor cells and their architectural growth patterns. Sometimes they can rely on immunohistochemical, some of the molecular properties or genetic profiles that put it in the proper subtype category.
Now the subclassification of RCCs and probably this is familiar. You’re familiar with RCCs and it is not so simple. It’s an evolving, sort of complex and ever-changing categorization. In fact, the overall categorization of subtypes just changed a few months ago. We like to think about RCC and subtypes in a sort of developmental pathway.
There is a sporadic type– that which just happened to occur–which is probably the type of cancer that most people in this room happen to have. Those are our typical clear cell, chromophobe, papillary renal cell carcinomas or maybe a few of the other rare variants.
There are those which tend to be familiar; these represent 90+ percent of all RCCs. The familial patterns–again what is associated—they are pretty rare. They are associated with and in families, multiple tumors. Different family members can have these, and we will talk a little bit more about these. There is actually going to be a talk about later in the afternoon or the morning about genetic-based or familial-based RCCs.
There are those rare—really associated with treatment of other types of cancers, and there is unusual category when you have scarred or damaged kidneys. Those kidneys are at risk for developing RCC.
Let’s move through this little bit. Once we have made the diagnosis of RCC, we’ve sub categorized it. I know it seems complex, but there are really only three or four main subtypes that we really need to talk about, especially in the context of a setting like this.
8 The most common subtype is the clear cell type. This represents about the vast majority of all sporadic types of renal cell carcinoma. Then there are the papillary and chromophobe renal cell carcinomas. Since these are really the usual types. The much less common type is collecting duct carcinoma which is really more like a urothelial cancer, it behaves like a urothelial cancer, it’s a more aggressive type of RCC.
These are really the main four that we need to be concerned about. They are each unique based on their gross appearance and these are all partial nephrectomies (this is complete down here). Look at their gross appearance. They are very unique under the microscope. Look at their microscopic appearance.
The clear cell is clear, the papillary, very architectural pattern of a papillary tumor. These are chromophobe. This unusual eosinophilic cytoplasm are the tumor cells. Probably doesn’t mean a lot to you, but it means a lot to us, also to some other clinicians. So they have very characteristic gross, microscopic and they are very unique biochemical—and as Dr. Kim alluded to—very specific molecular and genetic profiles as well. This is all really evolving as we speak.
And we all know—this is small graph—that these also behave differently, Some behave better than others, so it is really important that we subclassify these RCCs based on their appearance—all the appearances that we talked about.
9 The other thing that Dr. Kim alluded to, and I think we are going to talk about this a little later, and I won’t get into detail on this, but just to point out that the sub-classifications, the sub-categories, they respond differently to the different armamentaria that we have in terms of treatment modalities. So it’s very important for the pathologist to sub classify the type of RCC.
10 So on any standard pathology report, you are going to see the diagnosis, RCC, then the subtype, buried somewhere in the report; It will say, clear cell type, papillary type, chromophobe. That’s a very important part of the report.
11 After diagnosis, the next important aspect is the cancer stage; The cancer stage is really defined by the size of the tumor and its local growth. Is it extending, is it staying confined to the kidney, outside the kidney to the local fat, is it going into any regional lymph nodes that might have been removed during surgery, or was it extending into the adrenal gland, which might have been removed as well? So we analyze each case on what we have and what we see.
This is a typical example of a partial nephrectomy specimen of clear cell carcinoma with a margin that’s out here. Here it measures about 2.1 centimeters the margin is negative. This is a very small tumor of clear cell RCC. This would stage out at T1a, pretty low stage tumor. This would have a pretty good prognosis based on that staging profile.
12 Now compare that with this tumor which is a complete nephrectomy specimen, shown the kidney, a lot of nephritic fat. Here’s the sinus of the kidney and here’s the tumor out here. Much bigger, about 9 centimeters and it is growing into the fat. It’s growing into the sinus fat; it is demonstrating more aggressive local growth. This would stage out—this is a microscopic showing it extending into fat. We would stage this out at T3a tumor, as it is obviously larger and more infiltrative.
13 A different example would be the same thing. A RCC clear cell type; this is a full nephrectomy specimen. Here’s the kidney. Notice that the tumor is extending into the renal vein. This is another feature that we analyze and look for. We look for it grossly and microscopically and look for tumor extension into that vein, because that will upstage the tumor, overall tumor stage, and this is associated with generally adverse outcome. It is telling us this tumor is behaving more aggressively with local growth. We might see a lymph node, with metastatic clear cell RCC. Again, another aspect we would examine grossly and microscopically.
15 So we take all these features, once we have analyzed the tumor and we apply the grading system created by the Joint Council on Cancer Staging, the AJCC and we apply the pathologic stage. Why? Because as Dr. Kim alluded to, we all know, that cancer staging, and it is true for any type of cancer, the higher the stage, the more aggressive that tumor will likely behave therefore the therapy needs to be tailored to their particular stage. And the report should indicate clearly dictate the tumor stage. And that’s part of the standard reporting. Any good cancer report.
14 The final cancer features I’m going to talk about we’re talking about are; resection margin, the grade, vascular invasion, tumor necrosis and this this unusual rhabdoid or sarcomatoid differentiation. These are elements which go beyond cancer staging and the diagnosis. Here’s two examples.
16 Let us talk about resection margins. These are indirectly related to or they indicate the local aggressiveness of a tumor, if they are growing to a margin. It’s ideal when a partial nephrectomy or a complete nephrectomy is performed, as we have here, the surgeons always try to get the whole thing out so we achieve negative margins . That is optimal. Sometimes it’s not possible, especially if we have a high stage RCC like this one which is extending into fat. Sometimes it’s impossible to get a clear margin. This might get portend some additional therapy when it comes to therapeutic– time for a therapy . With a smaller resection sometimes it’s impossible to get a negative margin or the surgeon needs to go back and take cleaner margins. That interpreted for frozen section analysis, and clear out that margin, again because optimally, we want to achieve a negative resection margin.
17 The next factor is vascular invasion. When the tumor invades into those lymphatics that Dr. Kim talked about in surgery. They have a propensity for them to go to the lymph node or they can go into veins or even sometimes arteries and then they have unfortunately, the capacity to go to the lungs or bones or other sites. Those confer an adverse prognostic indicator. Those are an indicator that this tumor might behave in a more aggressive manner. So if we see it microscopically, we include it in the report. Also if there’s tumor cell degeneration and necrosis, that is usually associated aggressive growth in the tumor and we will report that, too. Sometimes that will dictate how the next round of therapy will be undertaken.
18 Dr. Kim already talked about tumor grade. We apply–the pathologist applies the tumor grade. The Fuhrman grade is the one that is used for RCC, and it a grading system for 1 to 4. Really, it delineates the degree of differentiation. Grade 1s are well-differentiated tumor, grade 4 are poorly differentiated and in any type of tumor–doesn’t matter if it’s breast, color, renal cell carcinoma–generally well-differentiated tumors behave better than poorly-differentiated tumors.And we assign a grade based on our observations.
19 Finally, sarcomatoid or rhabdoid differentiation. Most tumors will have just one type of differentiation. This is an example of RCC. The vast majority are RCCclear cell, the conventional type. But in it, there were some pockets where the tumor cells had this unusual morphology under the microscope, called sarcomatoid differentiation, or over here, with we had this rhabdoid differentiation. You can see it that it’s very different than clear cell. These, for whatever reason, are associated with tumor aggressiveness. So when we see this, we need to report it. We need to quantitate it, and we put it in the report because these mandate some additional therapy, independent of stage, because they are really associated with aggressive tumors
All these last category features that I talked about, once we have observed them, we include them in the report. Again, usually any standard RCC report will have these features included in them because they will really impact upon therapy. *See slide10
20 Two quick categories and I will be done here.I was say a couple of words about hereditary genetic syndromes associated with RCC. This is taken out there that long list that \I presented a few slides back. We all know that there are well-known, well-defined syndromes–genetic syndromes or familial syndromes that put you at increased risk from dying from other neoplasms, including RCC, notably Von Hippel Lindau, tuberous sclerosis, Birt-Hogg Dube, these sorts of things. The bottom line: as a pathologist, I can’t look at most of these tumors and say, “this is a clear cell carcinoma. It’s clearly Von Hippel-Lindau, tubersclerosis, or whatever.” All I can say is that it is clear cell carcinoma.
21 There are a few types of tumors that I can look at and say, if they have unusual morphology, like this tumor up here, or this tumor up here (references images) , they don’t comfortably fit into the typical types of RCC. Maybe it is a syndromic-type of carcinoma. Very, very rare, less than one percent that we would ever suggest to a clinician that maybe this is syndromic. What we can do is when we get samples like a renal resection like these three different cases, where there are multiple tumors. Here we have multiple tumors or multiple cysts—here we have maybe 20 or 30 different tumors in the particular kidney—or here’s a younger patient with one, two, three separate tumors. Then we can suggest that there is something odd about this, as we usually don’t see this in sporadic type tumors. Maybe it is associated with a genetic syndrome. So; multiple tumors, cysts, a young age, presentation of a renal cell carcinoma of unusual histology, we will suggest to your treatment team that maybe this is a genetic or syndromic pattern of RCC. There’s going to be more on this topic later this morning.
22 The final topic I was asked to talk about the performance of secondary slide reviews. It’s kind of important. It’s really important when you come to an institution for definitive therapy, it’s always good to have that team—and we do this all the time—review the outside slides to be sure that you have an expert team who works with your treating physicians. We work as a team through tumor board reviews and discussions, and almost every discussions–. Almost every single individual case, to ensure that we have the correct diagnosis. We have the critical elements included in that report. The specific special testings have been performed, and we have accurate diagnosis and staging and things like that. What you need to do is provide, when you come here, is a copy of the reports, a set of the glass slides, sometimes we call them the recuts. That is all we need to provide an incoming secondary review.
The other scenario when you go off, you might need to off somewhere else for some additional testing for some additional therapy. In that situation, you might need to take, or you should take a set of slides with you to that institution because they will probably want to the same thing and review to ensure that we are all talking about the same disease process.
Remember that your slides or blocks, when you are treated here, or whatever institution, generally those tissue blocks are stored in an incredible huge file, either in the basement of the hospital right below us here or in a warehouse as we have done down in Torrance. T. They are basically saved forever. So when you need to go somewhere in five or ten or fifteen or twenty years, God forbid that there is a recurrence, and you need to get some additional testing, we can pull those blocks out from Torrance (CA) and create a second set of recuts, or a third or fourth set. We can send it off wherever it needs to go for some additional testing or evaluation.
23 What you need to do is fill out this authorization form here at Cedars if you are being treated here at Cedars. All you need to do is check off “Get a copy of the pathology report” and please provide a set or recut. It’ll take a few days, three days. We’ll get that for you, send it where it needs to go, or we can give it to you directly and you can just carry it with you to that next institution or wherever you need to go.”
With that Dr. Luthringer thanks the KCA, the audience and Dr. Figlin for the chance to speak. And with that, I agree remind you to get a copy of your own pathology report, and know where your slides are stored. If there is any questions as to your own pathology, if the tumor seems to be unusual, or of an especially high grade, do yourself and your family a big favor, and discuss whether a review of your slides is in order!
With this rare disease, and the complexity of doing the kind of analysis you see here, do not be afraid to get that second opinion. Go back and see so that pathology may affect the treatment options given–very important!
The following is the transcription of the above YouTube video, explaining how DNA sequencing of tumor cells can guide treatment. Thanks to the University of North Carolina for posting this. A terrific explanation. (And it’s OK to view it a few times!)
“You were composed of cells–lots and lots of cells. Each of your cells contains DNA which is its instruction manual. If you are exposed to lots of things that cause cancer, so are your cells. If you lay in the sun, your skin cells get burned. If you smoke cigarettes, your lung cells get their nicotine fix. Exposure of cells to carcinogens can damage their DNA. Sometimes when cells divide, DNA can be damaged–just by bad luck.
Damage to DNA is usually repaired, but sometimes it is not. When damaged DNA goes unrepaired, the cells receive bad instruction, and can turn from a healthy cell to a cancer cell. Cancer cells divide too fast and crowd out other cells and grow with they are not supposed to grow. When cancer cells cling together, they form a tumor that might be found by a doctor or a patient.
Today most patients are treated based on what a piece of tumor looks like when viewed under the microscope. This is how oncologists have done it for 50 years. While this approach is better than nothing, it doesn’t work that well. Even if doctors agree what type of cancer a patient has, it does not always mean it is clear what is the best therapy to treat that patient’s cancer.
Recently, it has become clear that the cells instruction manual the DNA determines how s the cancer will to behave and in particular, it determines if it will grow quickly or slowly, if it will respond to one kind of therapy or another, and if it will be cured or come back.
Given that the cancer’s DNA is so important in determining how it will behave, doctors and scientists at the UNC Lineberger Comprehensive Cancer Center have determined to treat patients based on their and their tumor’s DNA. This approach relies upon new DNA sequencing technology, called massively parallel sequencing or next generation sequencing. So we call the Lineberger effort “UNseq”.
Here’s how it works. When a patient with cancer comes to UNC and agrees to participate in our study. Some normal DNA is taken from the patient, usually their blood and some DNA is collected from the tumor. From the tumor DNA and normal DNA are broken into smaller pieces and the importance pieces of the DNA are captured. This capturing is important so we don’t have to sequence all the DNA of a patient, just the DNA which is important in cancer. It is like going into a gigantic library and choosing the one book on cancer ignoring all the other books on eye color or heart size or height.
The captured DNA from the tumor and the normal tissue are then processed using next generation sequencing. After sequencing, we have two gigantic books of DNA sequence. One is the tumor’s DNA and the other is the patient’s normal DNA. Although the captured DNA is much smaller than the patient’s entire genetic sequence, each book is still several million letters long.
The tumor DNA book and the normal DNA book are then compared letter by letter. In most places the books are the same, but in a few places the letters are different. These differences represent mutations in the DNA, that resulted from DNA damage. Finding all the mutations involves a lot of math, but eventually, UNseq identifies all the mutations that are present in the cancer cell and not in the normal DNA .
Just having a list of the mutations is not the end, however. Only a small number of the mutations change what the cancer cells do. Most mutations are harmless. Whether a mutation is good or bad, largely depends on what gene it affects and what part of the gene it affects.
Once the list of mutations has been identified, a team of doctors sits down together and review the mutations at the molecular pathology tumor board or the MTB. Each mutation is reviewed. Some mutations are clearly innocent. Some mutations are clearly bad. For some mutations, it is unclear of their importance and the MPB not always certain what to do with these.
This is all done by doctors were not directly involved in the patient’s care, s so that similar decisions are made about the same cancer.
Once the bad mutations are found, they are confirmed by another clinically approved test. Information about the mutations that are confirmed is given to the patient and their treating doctors.
With this knowledge, the patient’s care can be more tailored or focused. The doctor may decide the patient to try a different therapy. The doctor may decide that the patient has a better or worse chance of recovery. Sometimes the DNA looks makes the cancer look like a different cancer than was found under the microscope. New treatment plans based on DNA sequencing are called targeted therapy.
Importantly, UNseq does not put patients at risk. If there is a good therapy for their cancer, they get that therapy. UNseq only changes care for patients who do not have any good options left. Unfortunately, that is a common problem for cancer patients.
Some day soon, we believe all cancer treatment will be targeted, that is based on what the tumor DNA, rather than what the tumor looks like under the microscope.
Doctors at UNC recognize that technology moves at a rapid pace, but applying new technology to patients can be slow for patients with advanced cancer. Having successfully implemented UNseq, UNC physicians are building upon the approach to develop a range of advanced tests for patient care. We believe that these new approaches will help patients with cancer live longer and better lives.”
I was dying ten years ago. My kidney cancer had moved into my lungs, threatening to choke me to death.The tumor and kidney were gone, but 100s of tiny lung metastases were growing. Lucky to get an FDA-approved immune therapy, high dose interleukin 2, my own system destroyed the cancer. Thus, I am intrigued by all things about the immune system and cancer research. “Adaptive immunity in cancer immunology and therapeutics”is one of the most comprehensive explanation of the tumor cell/immune system interactions–that I can somewhat(!) understand.
My summary is below, a more patient-friendly version. Don’t hesitate to take on the original, via the link! It is just the kind of article to take to your doctor to discuss immune response meds/treatments. It begins with the “abstract”, a summary of the information to follow.
Abstract: The vast genetic alterations characteristic of tumours produce a number of tumour antigens that enable the immune system to differentiate tumour cells from normal cells. Counter to this, tumour cells have developed mechanisms by which to evade host immunity in their constant quest for growth and survival. Tumour-associated antigens (TAAs) are one of the fundamental triggers of the immune response. They are important because they activate, via major histocompatibility complex (MHC), the T cell response, an important line of defense against tumourigenesis. However, the persistence of tumours despite host immunity implies that tumour cells develop immune avoidance. An example of this is the up-regulation of inhibitory immune monoclonal antibodies in clinical practice have been developed to target tumour-specific antigens. More recently there has been research in the down-regulation of immune checkpoint proteins as a way of increasing anti-tumour immunity.”
Immune Responses in Tumors—A Quick Summary by Peg
Since cancer cells are genetically different from normal cells, they also produce different substances—antigens—which can make them more noticeable to the immune system. Any antigen will generate a response from the immune system—think how the body reacts to an infection, an insect sting or a splinter.
Antigens trigger the immune system into action, keeping abnormal cells from taking over the system—most of the time. To grow, tumor cells develop inhibitory responses to limit or down-regulate those immune responses. An over-active immune response can be problem, well-known to those with severe allergies or auto-immune diseases like lupus. Keeping the proper balance is the norm for the immune system, despite ongoing external and internal changes
Using knowledge of these interactions to support the immune system, researchers have develop agent/medications. These are intended to strengthen the beneficial responses, and to prevent the tumors from suppressing or down-regulating those desired responses. Some monoclonal antibodies can effectively target these tumor-specific antigens and trigger tumor death or inhibit such growth. Some of these new agents include bevacizumab (Avastin), rituximab (Rituxin), alemtuzumab (Campath or Lemtrada), bortezomib (Velcade), denosumab (Xgeva) and trastuzumab (Herceptin), among many others, and for a variety of cancers.
Be aware that these agents may be called by the brand name, as Sutent, or the scientific name, as sunitinib, and may have several brand names for different cancers. Just another new challenge to all of us newbies.
Tumors exist with a system of structures, various types of cells and with a chemical signaling process. These shifts away from the normal cells and organs produce tumor antigens. The immune system notices the antigens and works to destroy the foreign cells. Then the tumors shift to counter the immune response in an endless signaling battle. It is a dynamic “fail-safe” system, with multiple checks and balances, work-around pathways, evasive signaling, and constant testing to maintain itself. When this system does fail, a tumor can be established and move to different sites.
Solid tumors have a tumor core, a margin that is invading into a healthy structure–blood vessels or layers of an organ–and lymphoid components. This can vary patient to patient, despite the seeming similarity of tumors, and vary from one metastatic tumor site to another. Inside the tumor will be the immune-cell types–macrophages, dendritic cells, natural killer (NK) cells, mast cells, B cell, and T cells. Different immune cells can be found in different parts of the tumor, and the variation and the density of these cells may play a role in clinical response. It may be that this reflects the robust nature of the natural response to the tumor invasion, or reflect that the system is being overwhelmed by the tumor. Others think that the infiltration of immune cells can be utilized the support of the treatments given to the patient.
The linked journal article goes into detail as to the various types of responses, including adaptive immunity, immune editing and immune evasion. In summary, there are numerous approaches to limit tumor growth within the complex system of antigens and immune responses.
As immune cells infiltrate a tumor, that infiltration can be measured. What is the meaning of a higher or lower level of immune cell infiltration? The following paragraph sums up the challenge of using tumor infiltration as a marker of prognosis or treatment response.
It is a commonly held belief that infiltration of immune cells into tumor tissues and direct physical contact between tumor cells and infiltrated immune cells is associated with physical destruction of the tumor cells. That can reduce the tumor burden, and improve prognosis. An increasing number of studies, however, have suggested that aberrant infiltration of immune cells into tumor or normal tissues may promote tumor progression, invasion, and metastasis. Neither the primary reason for these contradictory observations, nor the mechanism for the reported diverse impact of tumor-infiltrating immune cells has been elucidated, making it difficult to judge the clinical implications of infiltration of immune cells within tumor tissues. J Cancer 2013; 4(1):84-95. doi:10.7150/jca.5482
Tumor Infiltrating Immune Cells—a Good Sign or Not?
If the immune system is at work, immune cells infiltrate the tumor to work directly against the tumor cells, is the tumor destroyed? Does the body naturally destroy the tumor? Does the patient benefit from medical treatments which support the immune system? Unfortunately, the presence of the tumor-infiltrating cells can mean very different things, with a better prognosis in one type of cancer, and a poorer prognosis in another.
Monoclonal antibodies can target antigens in blood cancers and solid tumors. In blood cancers, antibodies counter several cluster of differentiation (CD) markers, and in solid tumors, growth factors such as EGFR (epidermal growth factor receptor) or angiogenesis factors, such as vascular endothelial growth factor (VEGF). The mechanisms of action can lead to direct cell death, or simply impede its growth or inhibit checks on the immune response.
Normal cells are naturally programmed to die, but cancer cells do not “follow the program”. When certain proteins on the surface of cells bind with one another, the expected immune response is inhibited. These anti-PD-1 (anti-Programmed Death-1) proteins bind with other proteins, the binders or ligands, PD-L1 and PD-L2. Studies indicated these agents can help the immune system, with some disease stabilization or tumor shrinkage. Recent trials show some response by 20-25% of patients, some of whom had failed previous treatments. Some responses lasted more than a year. In a few cases, some responses were lasted for a period after stopping the medications. Newer trials will likely combine several of these therapies. This is not without risk, as some had severe side effects, and several patients died from such side effects.
Nevertheless, the earlier successes with this approach and the increased knowledge of the various immune responses to be targeted will continue, especially in combination studies. This work will have impact on existing immune therapies, as does the more integrated approach to cancer treatment.
I welcome any comments and corrections, and remind you that I am a patient, and am not a medical professional. My goal is to help educate other patients to receive the best understanding of their illness and best possible treatment.
We continue to hear about gene sequencing and personalized medicine, and yet few of us really understand what they really mean–even if we have heard a lot about it. We also hear about targeted therapy, and besides thinking that the doctors had better be targeting the tumor as a minimum, often that is a real mystery, too.
The University of North Carolina has been doing some critical reviews of clear cell kidney cancer, trying to understand why there is such wide variation in the aggressiveness of clear cellRCC. Clear cell RCC looks the same under the microscope, the usual “pathology” report, but tumors can be shockingly different as to their ability to grow and endanger the patient. This can be true for a number of cancers, not just kidney cancer.
The obvious answer is that these tumors are not really the same biologically, which can be revealed by an inside look at the tumor and patient’s normal DNA. This is what gene sequencing can do, i.e., help define what differences exist in the tumor cell, which is essential in “targeting” the treatment to the tumor.
The following is a straightforward way to understand these new terms, and perhaps to give some great appreciate for the challenge faced by researchers, clinicians and patients in getting proper treatment.
https://www.youtube.com/watch?v=Y9HumO20GKc A transcription can be found in “Genetic Sequencing for Dummies and Me”
It is at the University of North Carolina that Dr. Kimryn Rathmell and her colleagues have created a test which can differentiate the more aggressive form of clear cell kidney cancer from a less aggressive form. This has critical impact on the decision to operate, to treat a smaller tumor, and to monitor one which has greater aggressiveness.
We have learned that it isn’t just “cancer”, nor just “kidney cancer”, nor just “clear cell” or “papillary” or “chromophobe”, but instead a molecularly defined cancer which has taken up residence in one’s kidney. Different strokes for different folks, and different targets for different testy genes in our tumors!
For years, doctors have debated one another about what to do with little kidney masses, i.e., “small renal masses or SRMs” in doctor-talk. Patients hear this debate only when it applies to them, or if there is some hysterical headline about tumor cells escaping the tumor because a biopsy was taken. What is the reality, and what value does this have to the patient?
First of all, most large tumors/masses on the kidney are found by CT or other imaging. In the kidney tumor world, large can mean
For years, doctors have debated one another about what to do with little kidney masses, i.e., “small renal masses or SRMs” in doctor-talk. Patients hear this debate only when it applies to them, or if there is some hysterical headline about tumor cells escaping the tumor because a biopsy was taken. What is the reality, and what value does this have to the patient?
First of all, most large tumors/masses on the kidney are found by CT or other imaging. In the kidney tumor world, large can mean anything over 3 to 4 centimeters in size. Taking out my inch ruler with its handy centimeter imprint, I see that is just over an inch to about 1 1/2″ in size. Might be the size of a walnut to so–still doesn’t belong there, nor sound too insignificant to me!
Nevertheless, that is a Small Renal Mass, and is not even considered for treatment by some doctors. Our newer and more frequent imaging can find tumors of this size, long before they would be felt by a patient. They may or may not ever grow much larger, or do so very slowly. In fact, about 25% of these SRMs are not cancerous. Rather reassuring, except for the obvious conclusion that 75% of them are indeed cancerous! Size doesn’t matter in this case! Add to that the possibility of that benign mass may continue to grow and mutate/change over time. Its benign character may not remain benign.
Some 10% of these masses may subtypes of RCC which rarely grow,and imaging cannot determine that. The patient may be too old or ill for surgery at the time of discovery. A rush to surgery may not be appropriate but can a biopsy answer some questions–and is that dangerous?
Some have raised a concern that inserting a needle into the mass to get cells to examine is inherently dangerous, and could release cancer cells into the body, especially along the track of the needle. Of course, any mass large enough to be seen is likely already sending out cells in the course of its growth. The chances of any such cell becoming an established tumor is incredibly small, but every metastasis got started from some ambitious and lucky cell landing on a fertile spot in the body.
The reality is that there have been very few cases of obvious tumor seeding along the needle path, as a biopsy is taken. And these biopsies can be very helpful in determining whether or not the mass is cancerous. Thus a biopsy should not be avoided, if there is a question as to the nature of the biopsy or if surgery is considered inherently dangerous.
But does the biopsy give all the answers? Unfortunately, it does not, and especially since the typical biopsy will not differentiate between certain of the newly-discovered subtypes of clear cell renal cell. In short, some clear cell tumors may be destined to be more aggressive, while others may be very slow-growing. This can be analyzed only by a molecular review of the cells, which is not done typically. Thus, even a biopsy–now thought to be far safer than in earlier years–may not provide a solid guideline for the next treatment. Getting the molecular analysis, as described in a previous blog about ccA and ccB variants of clear cell RCC, will become essential for patients in the near future. Or so I fervently hope.