Tag Archives: immune therapy

Durable Response to a Med: Long-lasting or a Hard Time? More Translation Required!

When you are suddenly thrust into the medical world, unwillingly and without any kind of road map, you are surrounded by poorly marked turns, meaningless abbreviations and the sudden shift in the dialect.  The Wellness Center is usually about having lost one’s “wellness”, a word used only in the medical world, and not by real people.

Pressed to make decisions that may change your life, for the better or worse, you can be confused by those clever new words, some  from the marketing people (see above) and others from the clinical side. It is critical to understand how familiar words get reworked to explain new concepts.  Such explanations rarely reach patients, who are numbed and deafened after a shocking diagnosis.  And in the medical “new-speak”, those same patients may be told that this is the time in which they must take charge of their health, and make wise decisions quickly and correctly.  I find this a cynical and self-serving approach, as rarely is any real education offered in the language of the patient.

In kidney cancer, we have been blessed with new drugs these past eight years, but have no clear way to determine which of these agents might be of benefit to any of us.  On top of the shock of diagnosis, the patient is thrust into a guessing game.  Even the doctor is forced to play along, and often neither party knows the rules or the chances to win.  The doctor may recognize the vocabulary used in this new guessing game, but the patient does not.  Words which have meaning in day to day life don’t work the same.  Even some of the goals of the game are unclear to the patient. Wait! You probably think that being cured is the goal.  you

For example, we patients think that “progress” is good, but that is not true in cancer.  Progression is the goal of the cancer, so Progression Free Survival (PFS) measures the time between treatment and when the cancer is on the visible move again.  The word “visible” is important here, as that is a reminder that cancer does not just start at a size or style to match the sensitivity of imaging.  X Rays cannot see things as small as a CT scan can.  Bone scans see bone mets better than other scans and so on.

In reading clinical trials, you will encounter “durable” to explain how long a median PFS can be.  It may be described as remarkably durable, but in the pre-patient world, we would think that is pushing into years and years.  In reality is may be 15- 18 months.  We happily grasp at any more months than the non-treatment reality may be, but be aware of your and your doctor’s expectations in durability.

“Durable response” is surely what we want, but that is not translated to a cure, which might be the patient’s interpretation.  When you hear that, do ask for clarification, “How long does that response last?  What do you mean by ‘durable’?  What do we do after the duration of response comes to a stop?”

Having a firm grasp of this term and all others is an absolute necessity, and even if that is hard–in the real sense–it will be worth it to you.  You will have greater understanding of the treatments, the disease process, and a bit more sense of where you are.

More on these topics later, but do track the language, and remember than you still speak the old language.  At the very least, be ready to question anything that has that new dialect sound to it!

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Adaptive Immunity in Cancer Immunology & Therapeutics–My Summary

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 immune system was revved up so as to destroy 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.

http://ecancer.org/journal/8/full/441-adaptive-immunity-in-cancer-immunology-and-therapeutics.php

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.

Peggy Zuckerman

peggyzuckerman@gmail.com

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Filed under Genomics & Genes, Immune Therapies Old & New, RCC Basics

Immunotherapy: A Trial by “Flu-Like Symptoms” and a Lot More

When I was diagnosed with Stage IV kidney cancer, I just assumed that the doctor would take some sort of medically-approved SMALL melon baller, scoop out the bad stuff, and send me on my way, never to sin/cancer again.  That was my first plan, and one which couldn’t be.

First of all, there is no medical melon baller, and certainly not for a tumor the size of a big orange.  No tiny key hole scar for me, but a large incision, and the removal of my tumor, my kidney, an adrenal gland, and  a few local lymph nodes for good measure. Though the scan seemed to indicate that the tumor was scrambling up my vena cava, a big vein heading toward the heart, the scan was more ambitious than the tumor.  The pathology confirmed that my cancer was “clear cell”, which was good, as it is the most common subtype of kidney cancer.

Bad news.  There were hundreds of tiny mets all over my lungs,  the CT scan showing tiny evil snowflakes throughout my lungs. “Too numerous to count”. Impossible to remove by surgery or radiation. Systemic metastatic disease–very bad stuff– and the reality that  visible mets were outnumbered by the tinier ones still unseen in a CT scan.  Only one medication was approved for advanced kidney cancer in 2004. It didn’t really work for many people, maybe just 7%, according to the clinical trials that had led to its approval 12 years earlier.

This treatment was High Dose InterLeukin 2, brand name Proleukin.  No one else seemed to have ever heard of it> When I asked if they had heard of  “interferon”, most people nodded politely.  That’s how much general awareness there is of the life-saving regimen recommended to me.  Most doctors and few oncologist have never seen a patient in treatment with it.  Not the popular choice–but none other treatments existed!

Statistically, the odds for a good response were pitiful, but so were the odds for my getting kidney cancer in the first place.  The “Why me?”s became “Why not me?  Someone has to be in the 7%!”.   I talked to a patient who had gone through the treatment. She described it as “Hell”. I winced visibly, and she nodded in sympathy.  Still she was alive and at a meeting. Given the chance, she said she would do it again!   Thank you, Paula, for your courage.

Proleukin is essentially a synthetic version of your body’s immune system reaction protein. Thus, the patient reacts with a wide range of immune responses–all in hopes of revving up the immune system so that it recognizes and fight off the cancer cells. Those cells have escaped detection by the immune system, disguised as “evil twins” of the healthy cells.  If the Proleukin could empower the immune system to be super sensitive and aggressive in finding the tumor cells, maybe the cancer would be destroyed.

This is not traditional chemotherapy, in which all the cells are targeted for destruction, with the fastest-growing ones–the cancer cells–being the most vulnerable.  Chemo patients are bombarded again and again, in a delicate balance between killing the cancer cells and keeping the others and the patient intact.  Many people stay on chemo for months and months. But no chemo ever worked for my cancer.

My treatment was to happen in five-day spurts, offset by days and home to recover and then to return.  Roughly, I was to be in the hospital one week, out a week, back in for a week, and then rest and await the verdict delivered by a CT scan.  Good news meant I could be permitted to return for another set of treatments.  Bad news–go home and look for another clinical trial and…no one wanted to speak of it.

My mets were shown to be fast-growing after a series of CTs , so even  stabilization of  growth would be considered ample reason to return to the hospital. ” Just slow them down”, I prayed, “Let me back in the hospital.” Determined that even if the doctor could not whole-heartedly recommend it, I would go back for more.  Of course, that was before I had the Proleukin and understood what would happen.

Had Proleukin not been effective for me, I would not be writing this. Still I have little independent knowledge of all that I endured during the treatment.  My family usually says that I am happier not knowing, that it was brutal, that it took me to the edge of life.  No wonder they don’t want to talk about it.  But I was in a excellent hospital, with experienced staff, having been considered to be healthy enough to get through the treatments, and determined to live, what ever it took.

This medication is delivered by IV, through a port which led a tube straight into my heart, a channel to get that and all other meds to me as quickly as necessary.  Doses are given every eight hours, unless the patient is unable to tolerate the next dose, needing to recover from the reactions to the previous.  Over the five day period, a patient might get 14 doses, though few ever do.  In my case, I received an average of nine doses per week, and my length of day was twice extendedby a day, so that I could recover before I was sent home to recover some more.

I remember arriving home, rather suddenly, it seemed. No memory of the drive, just a vague recollection of  walking down the hospital corridor with a doctor and trying to read a sign.  Apparently that was a bit of a test, which I passed, because I was home.  Home–to recover and praying do it all over again.

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Filed under About Peggy, Biological Systemic, Immune Therapies Old & New

Immunotherapy for Metastatic Renal Cell Carcinoma; David McDermott, M.D.

 Status of Immunotherapy in Metastatic RCC in 2012

(The lecture is from a patient conference, and may be seen by clicking through to YouTube. My transcription may make it easier to STUDY the information from Dr. McDermott and to review the slides.)

Dr. David McDermott; Dana Farber Harvard Cancer Center; KCA Conference

April 14, 2012; MD Anderson Cancer Center; Houston, TX

“This is a great opportunity to talk about this new research. The last six years brought great advances to the treatment of metastatic kidney cancer with newly approved therapies. No other area of cancer that has had made more progress with new treatments in that time, and there is more good news to come.

In this era of targeted therapies, some have asked if immunotherapy–once the only option for kidney cancer–has any role.  In the next twenty minutes, I will show you that it probably still does–for the proper patient.

Dr. Wood talked about limitations with the targeted therapies, the anti-angiogenesis drugs.  They are excellent at pruning the tumor, much like I do with my weed whacker. Though they can delay progression, and improve survival, you need to be on treatment to have its effect and all these tumors come back. Once you are off treatment, the effect wears off. They can delay progression, extend life and patients are living longer.

There has been a greater understanding about how the immune system works over the last 20 years when this was introduced.

The Immune System
Adaptive defense system that protects an individual from invading microorganisms
The immune system is specific
Involves multiple large polypeptides that function in:
     Antigen presentation
     Antigen recognition
     Intercellular signaling
Involves multiple cell types                                                           Slide 2

These insights can improve outcome for our patients. The immune system is a defense system, which protects the person from invading bacteria and viruses.  This system contains multiple moving parts and multiple cell types.

Here is a cartoon example of all the different cells and antibodies, which can protect against bacteria, others that can target a microorganism, or more importantly, a tumor cell.  This system was not designed to fight cancer; it was designed to fight infection. That means it is designed to turn on when you have an infection like a virus, and when the virus is controlled, the same “turned on” cells of the immune system are then shut off. These shutoff mechanisms are in part responsible why cancer can evade the immune system, and why it has been so difficult to use the immune system to fight the cancer, as opposed to fight infections.

Different approaches are being used with the immune system to fight cancer, some we’ve used in the past and some exciting new approaches currently being tested. The first approach is much like pressing on the gas. This approach to immune therapy has mostly involved cytokines, with interleukin 2 and interferon, and was used for a long time.  They rev up the immune system and are growth factors that stimulate a lot of the parts of the immune system, such as T-cells.

Dr. Wood said there were no home runs for patients for Stage IV kidney cancer, but that is not exactly true. There are very few home runs, a few patients with stage IV disease who obtain a remission of their disease. Remission means treatment of Stage IV disease in which the cancer goes away, treatment stops, and cancer does not come back. To most patients, that is their goal. Very few patients meet that goal, but for some that remission has lasted decades.

Pressing on the Gas of the Immune System

 It is also true that this “pressing on the gas of the immune system” does not work for most patients.  It is hard to identify which patients it will work for and is associated with lots of side effects.  To be effective, as with interleukin 2, these treatments must be given in a hospital. They involve serious side effects, sometime life-threatening side effects, so the kind of patient who can receive this type of treatment is relatively limited.

At Beth Israel Deaconess in Boston we try to be selective choosing patients for this therapy. We try to identify the patients who may receive the home run, before we put them through the side effects, because so many patients go through the side effects without benefit.

 High-Dose Aldesleukin “Select” Trial in Patients with Metastatic RCC
D. McDermott, M Ghebremichael, S Signoretti, K Margolin, J Clark, JSosman, J Dutcher,M French, and M Aktins on behalf of the Cytokine Working Group

We had clues about things that might improve the selection, so created the IL2 SELECT trial, reported at ASCO two years ago. The activity of IL2 in this era of these new treatments is still relatively good, as good as it was 20 years ago.  The response rate in this trial with 120 patients was 25%, significantly greater than it was when the drug was introduced 20 years ago. The drug is not any better, or are we any better at giving it.  But we are better choosing our patients. Choosing who should get it, and who shouldn’t, and that improves the responses of our patients.

It has been known that patients with non-clear cell are less likely to respond to immunotherapy, so in this trial there were very few patients with non-clear cell cancer—and no responders in that group.  It is also known that patients who had their primary tumor removed when they presented at Stage IV disease are more likely to respond to immune therapy.  In this trial, 99% of patients had that surgery before they went into this trial.  It is almost certainly true, that with new therapies available, that the types of patients being referred to an IL2 centers like ours is probably different.  Changing the types of folks we are treat means our numbers are improving somewhat.

To improve the selection process and based on earlier research, we wanted to show that certain features of the patient’s pathology of the tumor might predict for response. We looked at what the tumor under the microscope and special proteins (CA IX or carbonic anhydrase IX) that the tumor might produce.  We thought those things might predict either high chance for response or low chance for responding to treatment.

Unfortunately for me as a researcher, although fortunately for the patients who went on this trial, the folks who were in the poor risk group–those we thought would not benefit from IL2–did just as well as those not in the poor risk group. It surprised us and showed the importance of testing theories in the proper trials. We clearly need to do more work in this direction to find something to explain why some people benefit and some do not. And it may turn out that response may have more to do with the patient’s immune system than the cancer as how they benefit from treatments that boost the immune response to cancer.

RCC IL-2 SELECT Trial; Conclusions
Tumor features did not predict for response.
Efforts to confirm other predictors are ongoing.
Lessons from this work may guide the development of targeted immunotherapies in mRCC(e.g. CTLA-4, PD-1 antibodies)         Slide 9a

So in conclusion for this trial, the tumor features did not predict for response, but we had a higher response than we expected higher than 20 years ago.  This work continues and some of this work will educate us as we go into this new world of targeted immune therapy for kidney cancer.

So as discussed, the immune system is not designed to fight cancer, but to fight infections.  This graphic shows where the immune system turns on in response, and at its greatest, starts to shut off, as it is designed to do. The shut-off valves of the immune system–the brakes–are in some ways stronger than the gas pedal.

Releasing the Brakes

In the laboratory over the past ten years we have been able to identify what are those brakes are.  Now we ask how to block those brakes. One of the most important brakes on the immune system is a protein called CTLA-4 (CytotoxicT-Lykmphoctye Antigen 4). We can block the action of this protein, to release one of the most important brakes to immune response to cancer.

On this slide you see the T-cell on the left, an activated T cell, as it activates a protein, turns itself on. The same T–cell that turns itself on, puts out a protein on its surface, called CTLA-4.  When that CTLA-4 protein comes in contact with another protein on that cell, an antigen-presenting cell, it actually shuts off the cell, a natural way of shutting off the immune response. That way these cells don’t overreact to an infection and attack healthy tissues,  Now we can interrupt that interaction by bringing in a monoclonal antibody, which interrupts the connection between CTLA-4 and important proteins of the immune system.  So we can block the natural shutoff that many patients experience.

Does that work to clinical effect with kidney cancer patients?  The short answer is it does.  Data presented in the New England Journal of Medicine two years ago. Blocking this protein in melanoma gave improved outcomes, and this was an out-patient treatment, intravenous, given every three weeks for four doses.  It’s actually been shown to improve survival for patients with metastatic melanoma.

Blocking CTLA-4

And it’s not treating the cancer; it’s treating the patient’s immune system. The immune system is going out and detecting the cancer in ways that it might not have before getting this antibody.  It is outpatient therapy, but it is still associated with significant side effects.  Most of those are auto-immune side effects, where the body is now being attacked by its own immune system.  Some of these are been quite serious and patients have died from this treatment.  We are getting smarter at managing the side effects so there are fewer major complications, but do not get the impression that it’s not serious treatment.  It’s less toxic than IL2, can be given to more patients, but still has side effects.

Ipilimumab in mRCC
                                                     Single institution (NCI), Phase II trial
Major response rate of 9%.
Max dose test 3/mg/kg.     (Dose response in melanoma)
Survival effect in melanoma despite low response rate.
Additional studies alone and in combination warranted.           Slide 14

This data led to FDA approval last year of Ipilumimab, now called Yervoy. It was approved in melanoma, but it has been tried in kidney cancer patients at the National Cancer Institute in a very small 36 patients, phase II trial.  The response rate, the chance that the tumor shrank by half, was only 9% in this trial. That may not sound great, it was tested at a dose which may not be the right dose; higher doses of treatment may be tested in the future. In melanoma we saw improvements in survival and saw lasting remissions for Stage IV patients. We saw those benefits even with a very small response rate. Go to the “Blocking CTLA-4” slide, and look way out on the survival curve towards the end. These are patients out 3 and 4 years, still in remission and off treatment. That happened even though the response rate to treatment wasn’t very high.  It is possible that we might see a long-term benefit for some patients with kidney cancer with an agent like this. Some others are being tested in the coming year, so I would be thinking that additional studies with this approach are certainly warranted.

 Steering the Body’s Immune System

We need not just the “accelerator” and the “brakes” to make these things work.  We also need improved steering. Investigators want to improve steering by giving patients vaccine approaches. This may get patients’ immune systems to recognize proteins found on the tumor, to wake up and to go and attack those proteins, and to try to control the cancer. These approaches are now in phase III trials that have shown some encouraging results, where we will get some answers.

The agent AGS-003 is being combined with the most commonly used drug for kidney cancer, Sutent. Patients are randomized to use either Sutent alone or Sutent with this drug.  Whether this will lead to more response rates and to more long term benefit than with Sutent alone remains to be seen. At least we will get an answer from a large Phase III trial.  One of the problems with immunotherapy trials over the years is that they haven’t been large enough to give us clear answers. But this trial is enrolling patients and there are others like it.

 Putting up the Barbed Wire Defense

Since we’re in Texas, so I thought I’d give you a barbed wire analogy. One way in which tumor cells evade detection by the immune system putting up this “barbed wire” on their surfaces. When a T-cell comes, tries to sniff out the cancer cell, it is shut down, as opposed to going on to kill the tumor cell.  We now know a little bit about that natural barbed wire which comes into play with this particularly important protein interaction, the programmed death pathway, and what that stands for is the inactivation, or the programmed death of the T-cell, which acts like barbed wire.

Why is this important?  In kidney cancer, many patients’ tumors are coated with this barbed wire. Patients who have this on their initial tumor specimen have been shown to be more likely to have more disease recurrence in the future.  Since we can identify the barbed wire, can we block its activity and lead to an improved effect? The question is, can we target this protein and can we improve outcomes?  There is early evidence that maybe we can.  This is a Phase I trial, admittedly very early.

Programmed Death (PD)-1/PD-L1 Pathway: The Basics
Several tumor types, including RCC, have been shown to over express inducible PD-L1
Over expression of PD-L1 by RCC tumors has been shown to be associated with adverse clinical/pathologic features, including the following:
            More aggressive disease
            Shorter survival
            Also report to impair tumor immunity
             Can PD-1 pathway blockage head to clinical benefit?                          Slide 18

 

 Phase I Study to Evaluate the Safety and Antitumor Activity of Biweekly BMS-936558 (Anti-PD-1, MDX-1106/ONO-4538) in Patients with
Renal Cell Carcinoma and Other Advanced Refractory Malignancies. 

Patients received an outpatient treatment, intravenously, with a drug that doesn’t even have a name yet, BMS-936558, a PD-1 anti-body.  This is blocking the interaction between the barbed wire and T-cells.  In this trial it is given every two weeks; on other trials it’s been given every three weeks.  Patients were allowed to stay on this drug for up to two years as long as they were getting some clinical benefit.

SAFETY RESULTS; ALL PATIENTS
For the entire group, MTD (Maximum toxic dose) was not reached at doses of 1, 3, and 10 mg/kg
There was no apparent relationship between drug dose & AE (adverse effects) frequency
One treatment-related death 
Grade 4 drug-related pneumonitis                                                 Slide 20

The main reason to do a phase I trial is to test the safety of the drug. This drug was found to be relatively safe, and we got up to the highest dose without getting into serious side effects.  There didn’t seem to be a relationship between the dose and the side effects, which was good. There were still 10-15% patients who had serious side effects. In this group of kidney cancer patients and there was one treatment-related death, due to an inflammation in the lung that was probably contributed to by the drug.

  SAFETY RESULTS; ALL PATIENTS

Any grade, drug-related (investigator attributed*) serious AEs (SAEs) occurring at a frequency >1% in the entire study group (n=126)
            Total with an SAE=11%
            Investigations=3.2%
            Endocrine disorders=2.4%
            General disorders and administration site conditions=1.6%
            Hepatobiliary disorder=1.6%
            Neoplasms benign, malignant and unspecified=1.6%
            Respiratory, thoracic and mediastinal disorders=1.6%                         Slide 20a

 This trial of 126 patients was a much larger group and not just a kidney cancer trial with five cancer types in this trial. There are now 300 patients in this trial, and we’ll get more data in the next several months.  But in general the safety population is much larger than the efficacy population.  The main point here is that serious adverse events occur in about 11% of all patients, much less than in HD IL2 and CTLA-4.

What did we see in terms of effectiveness?  For the first 16 patients analyzed, we saw five partial responses (31.3%), and three patients (18.8%) with stability that lasted over six months. About 50 % of patients were getting some clinical benefit with this antibody. Once again, a small number of patients tested.

Here is an example of the patients we studied, a young man who was diagnosed in 2009, received IL2 and progressed, received Sutent and progressed, had disease in multiple places, including the kidney and the bones and lungs. You can see the before and after pictures after receiving two courses of treatment of ipilumimab with a significant response in the lungs, which is ongoing therapy after two years.

We’ve also seen responses in some unusual places.  One place that a lot of our VEGF targeted patients fail is in the bone. This is a patient, before and after, who had a response with a bone metastases you can see here (left scan), and actual healing bone (right scan), just a year later with treatment.  That’s certainly an encouraging result for us.

How long do these responses last?

For this admittedly small group, it looks like the major responses for a majority of these patients who had a response, that response lasted over a year.  Most who had a response still have that response at a year.  Whether that response will continue or stop, when the drug is stopped, remains to be seen. That will be a very important question. But the good news is the patients can tolerate this treatment for a year or more.

In summary, the PD-1 antibody concept is very early, but it has displayed reasonable side effects at all doses we’ve tested, and we seen some anti-tumor activity in some patients with kidney cancer.

PD-1 Antibody Summary
At this EARLY point, BMS 936558 has displayed manageable side effect at all dose levels tested
Anti-tumor activity observed in a small number of patients with RCC
            Responses may be durable?
16 patients added to this cohort-ASCO 2012
Responses in NSCLC
Trials launched in 2011 in RCC:
Dose finding Phase II study in patients with prior therapy
Biomarker Trial
Combination RX + VEGF TKI (Phase I)

Were these remissions, i.e., durable, or just responses?  Will the patients’ tumors grow after we stop the drug?  We don’t know that yet, but we’ve added 16 more patients to the study. We will present data at ASCO in two months (6/12), with more information on this anti-body soon.  It is important to note that with this drug and for the patients on it and for the field of immunotherapy for cancer that we are we seeing responses for kidney cancer and melanoma, where we’ve seen immune responses before. It is quite important also that we are also seeing responses in lung cancer. Should that be true, that will bring a lot of energy into the field going forward, as lung cancer is obviously a much more common illness, with very few options available.

There were a lot of new trials launched in 2011. We’ll have a Phase II trial in 2012, including multiple doses, to find the best dose in this treatment and also in combinations with other drugs like Sunitinib to find the best combinations.

So for those who say, “Is there a role for immunotherapy for RCC?” I would say there’s been a lot of progress over the last 30 years in the field of immunology, and we can now better target immunotherapy, and it’s worth preserving.

Is there a role for immunotherapy for mRCC?            There has been progress in the field of immunology in the last 30 years

            Immunotherapy can be “targeted”

            Immunotherapy is worth preserving                          Slide 25

There is a role for immunotherapies shown by survival curves like this; this is from the SELECT trial mentioned before.  These are patients who responded to treatment, now out three years, off treatment. The 13% percent of these patients, 16 patients have that benefit which really achieves the patient’s goal, which is worthwhile to try to get for more patients. It is proof of principal that we can do this, but we need to do it for lots more patients.  If we work on this, hopefully we can achieve Dr. Wood’s goal of more cures for kidney cancer, with targeted immunotherapy.

QED

Audience: Does the pathway of the targeted drug therapy have any impact on whether or not immunotherapy would have any effect on tumor growth or not? Different targeted therapies have different modes of blocking pathways.  Would that have impact, or has your research shown any impact on different pathways.

 Mc Dermott: “That is a very good question and not simple to answer.  Many of the treatments I talked about, like the cytokines, like IL2 or interferon or CTLA-4 work on the patient’s immune system-we think ONLY, only, meaning they are boosting the immune system to an established cancer.  For reasons we don’t completely understand, that is effective in some patients and not in others.  In the case of the PD-1 antibodies, they may be acting on the immune system, and may act on the tumor as well.  There is some evidence of that in the early research, as I mentioned with patients who have this barbed wire on the surface of their tumors, or have this pathway activated, or when this pathway is on, they may be more likely to respond to this approach.  Meaning, when the barbwire is up, and you can block its activity, maybe you can lead to an effective immune response.  And what that may say something important about the pathway, but it may also say something about the immune system’s response.  The barbed wire, we think, is up, as a reaction, a survival mechanism for some tumors. That is one of the reasons that cancer is so difficult to deal with, that there are so many different ways the tumor can evade the treatments. That barbed wire, that PD-1 may be one of those protection mechanisms.  So that means tumor turns on, the barbed wire is up when the immune system is there, you can’t kill it, but you can block the barbed wire, take these immune cells are right there and it can kill the cancer.  This may explain why some patients have a benefit and some don’t.  And we are now looking to see, if your tumor has barbed wire, whether you are more likely to respond to treatment.  There will be a lot more information about that in the future.  Good Question.”

 Question: I wonder if you knew if there was a clinical trial going on for prostate cancer, believe it is called XPl 4(sic), and its for bone mets, and if you knew anything about it’s work with RCC.

 McDermott:   “Re this med and RCC,I don’t treat prostate cancer, just melanoma and kidney cancer.  Is the drug you are talking about XL 184?  This is a drug that is in early trials, and maybe Dr. Jonasch will talk about it and similar drugs.  These drugs work in the blood vessels to attack the cancer.  They target two proteins, VEGF, which you’ll hear a lot about, and another protein which is important, C-MET, called MET inhibitors.  There has been interesting activity in prostate cancer with this drug in trial, and a very small trial we participated in Boston with this agent with kidney cancer patients.  You will see more info on this drug at the ASCO meeting in June and the info will be public on May 16.  ASCO publishes all its info, so you will be able to get your hands on the results from that very small trial in a very few weeks, which is good.  It’s a drug that has promise, but it has some side effects that need to be managed.  The fundamental question here is for the kidney cancer advocacy community, is it going to be tested in kidney cancer?  We are still not definite yet, but we are pushing to test this class of drugs in kidney cancer, this particular drug. We are pushing sponsors to do trials, but they are most interested in prostate cancer.  When those trials are to start and with kidney cancer, we are not entirely clear.  We need to push them to keep developing these interesting drugs for our patients.”  

 ME:  This is an extension of the question, as to how you choose the best patients who have the best chance of responding to IL2.  Does the histology or the pathology, and frankly I don’t know the difference between the two, have a major impact, and can you expand on that?

 McDermott:  “Yes, I may have gone too quickly on that.  We thought the answer was yes, and when it comes to big differences,  clear cell versus non=clear cell, it does, meaning when patients come to us, non-clear cell cancer for IL2, we will say to them, ‘It’s not going to help you, or the chances are so small, that the harm or potential harm outweighs the help.’  So to answer one of your questions, non-clear cell histology, which is simply a medical term for ‘What does this thing look like under the microscope?’.

 For non-clear cell histologies, we don’t offer IL2.  Whether one of these newer immune therapies work for that class of patients, should be tested because there is hope.  That is why I mention the lung cancer story, because if it can work in lung cancer, it might in one of these less common kidney cancer types.  It may work for many other forms of cancer.  So that is a hopeful thing and exciting.  But to take it a step further, while we thought clear cell cancer was more likely to benefit, we also thought it was that certain types of clear cell cancer were likely to benefit.  That is what we tried to prove in that trial, but we couldn’t prove it.  Doesn’t mean it wasn’t so, we just couldn’t prove it. We haven’t improved out selection ability based on looking under the microscope in ways that we had hoped.  We can do it a little bit, and that’s why the response rate went from 14% when the drug was approved to 25 % today, but it’s not enough, so patients don’t have to go through the side effects if they are not to benefit from the treatment.”

 Question; I don’t know if I know enough to ask a coherent question, but this is related.  Why would it be that certain tumor types or subtypes would respond to IL2 or not?  Is it because their profile of cell surface markers that let the immune system targets them better?

 McDermott:  “That’s actually a very sophisticated question, and one that does not have a clear answer.  It may be, one thing you mentioned, it may be that the immune system usually recognized proteins, usually proteins associated with infections like viruses or bacteria.  So it may be, as you point, that there are certain tumors that have show these proteins to the immune system better than others.  And then the immune system can detect these proteins and say, “This is something wrong here, let’s go kill it”.  That’s one possibility, and we tried to prove that in our trial, because one of the proteins we looked at was the protein called carbonic anhydrase IX.  We thought this protein was being recognized by the immune system and that might predict for benefit, but we couldn’t prove it.  So many people suggested your theory, which was that these proteins are important, but we could not prove it in this trial.  It doesn’t mean that there aren’t others that are important, we just couldn’t confirm it.  It may also mean that there are certain aspects of the tumor, that even though it is recognized by the tumor, something is preventing it from dying under the strain of an immune attack. That has to do with how well a cancer cell dies under stress. There may be some that don’t automatically shut down when they are being surrounded, that’s part of it.   There are also other important proteins that the tumor can make to avoid detection so the opposite of what you are talking about, that barbed wire analogy.  These are proteins that the tumor can turn on, and act like barbed wire, so that when the cells are coming it, they are turned off.  So there’s a variety of different theories and more than one aspect of that.  It’s a fairly complicated story.”

 Me; Back to CA IX, the fact that you expected that more of that would lead to greater response, you found the opposite to be true?

  “No, we didn’t find the opposite to be true, we found that the folks who had CA IX protein on their tumors did well, or better than the old numbers.  Those patients responded at about the 25%, but they did as good anyone.  What was different was that the patients who didn’t have CA IX on their tumor did just as well.   So that is why I said it was bad for the research, but good for those patients.  We would have assumed, if we hadn’t done the trial, that to those patients, we might have said, ‘You don’t have CA IX on your tumor, no IL2.’ We did the trial to show that, we couldn’t.  That means that going forward,, we should include those patients getting IL2.”

 Me:  I went on IL2, and I am a complete responder, and I had a relatively low level of CA IX, so I always watch that and wonder.

 McDermott:  “You are an example of why my research career is floundering,” laughing.

 Me; Sorry, but it works for me, works for me!

 McDermott:  “I am very happy for you and for those patients on the trial.  That is why you do the research.  The CA IX story, and this was scary when I saw it, actually made it into the medical training literature.  So if you were an oncology fellow, you learned that McDermott at Beth Israel and others said CA IX was important, and that high CA IX patients should IL2 .And then when I saw the results of the trial, I thought, O my gosh, this has become gospel, and is maybe not right. You are a perfect example of it, and it means we need to do more research into the area . You are an excellent plant could not have been better.”

 Audience: Did you say that you have some non-clear cell patients on the MDX trials? 

 “Not yet. Most of them whose tumor type we knew all have been clear cell.  But in some of the future trials there are small numbers of non-clear cell patients who will be enrolled.  If there is any sense of activity, it may encourage study sponsors/drug companies to develop it in non- clear cell patients.  They will not be excluded on trials going forward.”

 Audience: So you your knowledge there is not one which is limited (to non-clear cell) for MDX 186?

 “I haven’t seen a response in that category, since most of the patients are clear cell the assumption in the field is that clear cell benefits from immunotherapy, so when you try to prove a principal, they try to collect the patients most likely to benefit, so not to put people through treatment that will not benefit.  But now that we have this proven—really not proven—but a hint of effectiveness, different types of patients are being included in the trial.  For example, the trial which includes the addition of MDX agent with Sutent allows non-clear cell patients.  Hopefully there will be more of those in the future.  The good news is there is more than one drug company developing these antibodies, and I will include those in my talk this afternoon.

We don’t do all the work at our place, but I haven’t seen a non-clear cell responder at my place.  I have seen responses with very aggressive tumors, that had sarcomatoid features, for example, but I haven’t seen one with non-clear cell.  That does not mean that it has not occurred.”

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