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Killing Blood Cancer: CLL

Chronic lymphocytic leukemia or CLL is a blood cancer that typically occurs in older adults. There is no cure, but now doctors are studying a new treatment that could stop the disease in its tracks.

Every week, 75-year-old Ed Venneberg spends five and a half long hours driving from Phoenix to San Diego, "It is about 385 miles" Venneberg said.

Ed makes the trek so he can participate in a clinical trial testing a therapy for blood cancer.

Venneberg told Ivanhoe, "I think this is the fourth clinical trial I've been in."

The new trial is looking at a drug called Cirmtuzumab for a type of leukemia known as CLL.

Thomas J. Kipps, MD, PhD, Professor of Medicine at UC San Diego Moores Cancer Center told Ivanhoe, "This is the most common adult leukemia in western societies."

Cirmtuzumab is actually an antibody. It targets and attacks a protein that's normally only used by embryonic cells during fetal development. Scientists believe this same protein drives tumor growth and disease spread.

Dr. Kipps explained, "We have early data now to suggest this antibody may be effective at preventing the relapse and metastasis of cancer."

The clinical trial is a Phase I study. The antibody is given as an infusion every two weeks. Doctors believe the treatment may also help cancers of the ovaries, lungs, breast, colon, skin, and pancreas. Ed hopes the treatment will be the answer he's been waiting for.   He said, "I think there's a good chance with this drug." He says it's well worth the drive!

The antibody was developed in the lab by Dr. Kipps and colleagues. The clinical trial will accept patients with relapsed or refractory CLL. For more information about the study, log onto www.Ivanhoe.com.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow, where blood cells are made. In CLL, the bone marrow cells become cancerous and do not mature or die when they should. Eventually, the cancer spreads into the bloodstream and to other organs. The term chronic means that the cancer develops slowly and is typically harder to cure. A genetic mutation in blood-producing cells causes a certain type of white blood cell, called a lymphocyte, to be abnormally formed. Lymphocytes help the human body fight infections, and when it is deformed, it becomes useless. The deformed lymphocytes can accumulate and crowd out healthy cells in the blood or other organs, causing damage or complications. CLL primarily affects older adults and accounts for about 25 percent of new cases of leukemia. Treatment for CLL may involve chemotherapy, drug therapy, and bone marrow stem cell transplant depending on the stage and severity of the cancer.

(Source: http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-what-is-cll, http://www.mayoclinic.org/diseases-conditions/chronic-lymphocytic-leukemia/basics/risk-factors/con-20031195, http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-key-statistics )

SYMPTOMS: Because this type of cancer is chronic, many people don't notice any early warning signs. However, when the cancer has progressed some symptoms include:

·         Fatigue

·         Fever

·         Night sweats

·         Enlarged, but painless lymph nodes

·         Pain in the upper left part of the abdomen

·         Weight loss

·         Frequent infections

(Source: http://www.mayoclinic.org/diseases-conditions/chronic-lymphocytic-leukemia/basics/symptoms/CON-20031195 )

NEW TECHNOLOGY: Researchers at UC San Diego are developing a new drug to treat CLL. The drug, cirmutuzumab, is an antibody designed to attach to a protein on the surface of CLL cells. Researchers hope that this process will block cancerous cell growth and survival. Right now, cirmtuzumab is being tested for its safety and effectiveness in humans in a Phase One clinical trial.

(Source: http://www.utsandiego.com/news/2014/sep/17/ucsd-leukemia-cll-trial-kipps-cirm/https://clinicaltrials.gov/ct2/show/NCT02222688?term=cirmtuzumab&rank=1 )

FOR MORE INFORMATION ON THIS REPORT, PLEASE CONTACT:

Jacqueline Carr

619-543-6427

jcarr@ucsd.edu

If this story or any other Ivanhoe story has impacted your life or prompted you or someone you know to seek or change treatments, please let us know by contacting Marjorie Bekaert Thomas at mthomas@ivanhoe.com

Thomas J. Kipps, M.D., Ph.D., Professor of Medicine at the University of California San Diego, talks about a brand new way to target and kill blood cancer.

Interview conducted by Ivanhoe Broadcast News in November 2015.

Can you explain what CLL means?

Dr. Kipps: CLL is Chronic Lymphocytic Leukemia and is the most common adult leukemia in Western societies. It's a disease that typically occurs in the sixth and seventh decade of life, but can occur in patients in their twenties. It has been considered non-curable. One of the fascinating aspects of this disease is that the clinical course can be varied depending on the patient. Some patients may have fairly aggressive clinical courses and some patients may have more indolent clinical courses. Even with the advances in chemo-immunotherapy, we still don't have a defined curative treatment strategy for patients. So, you can imagine the frustration if you are approaching sixty and seventy years of age and you're looking forward to some retirement years and get diagnosed with leukemia. You'd like to know that there are some options available for treatment. I've spent a career researching chronic lymphocytic leukemia. The main reason for doing this is that early on in my career, I made a choice that I wanted to study the actual cancer cells. With leukemia, I could just get a simple blood sample and then take apart the disease and compare it to normal cells. We've learned so much about this leukemia that it's really led to advances in therapy which are now yielding fruit. We have four new agents that have been approved over the last year, so there's been tremendous progress in the treatment of patients with this disease.

Is it all chemo-based?

Dr. Kipps: No. We're getting away from chemotherapy. I think chemotherapy has its place, but it's like a one trick pony. We know how it works and there are some limitations in cells. Through next generation sequencing, when you treat a patient with chemotherapy, you actually select out those small numbers of cells that have resistance to the chemotherapy. They repopulate the leukemia in such that the leukemia becomes resistant to chemotherapy. Unfortunately, the body is still sensitive to the effects of chemotherapy, so you can see it's not a very good situation to be in.

Are you leading a new clinical trial?

Dr. Kipps:  That's correct. We've been advancing the idea of immunotherapy for cancer for some time. Some years ago, we actually had the idea that leukemia cells are a category of cells of the immune system. They're a type of cell that participates in the development of immune responses. We noted very early on that these leukemia cells were able to put to sleep a healthy immune system. You put them next to normal T-cells and the T-cells go to sleep. This was disheartening, but indicated that there may be fascists of the leukemia that they're trying to hide. We looked very hard to develop strategies that could activate the immune response in patients with this leukemia. We developed a gene therapy approach where we actually transferred a gene into leukemia cells that could activate the immune system. Then, we were able to give the cells back to the patient. We took the leukemia cells out, activated them and then gave them back to the patients. We looked at these patients and at other patients that were treated and found that some patients made antibodies against their own leukemia cells. These are proteins that can bind to the leukemia and you can detect them, but what's fascinating is that they bound to the patient's leukemia cells and to an unrelated patient's leukemia cells, but didn't react against normal cells. So, this may be a specific marker for leukemia cells.

How did you proceed with this data?

Dr. Kipps: The protein that we characterized was one that we actually noted through gene expression studies a few years earlier. This protein was actually an embryonic protein, a protein that was expressed during early development. During the development embryo, you actually turn this protein on and then it turns off during fetal development and then is silenced in adult cells. For some reason, the leukemia cells turn this protein on. Since then, we've been able to figure out that this protein actually does serve a purpose. We noted that it serves as a receptor and tried to develop assays to see if we could test some of these antibodies against this protein and block functioning. One thing we found is that a few patients that made antibodies against this protein made antibodies that really blocked the function. That gave us a clue that maybe we could develop in the laboratory antibodies that mimic the antibodies that were made by our patients.

What was the outcome of this antibody development?

Dr. Kipps: We made many different hybridomas to make new clones and actually found one that was able to block the function. It turned out to be a fairly low affinity antibody, but it didn't bind too well to the right area. This antibody could block the function of this protein. Based on that, we were able to work with the California for Regenerative Medicine and they provided funding for humanization of that antibody and making higher affinity antibodies. We actually were able to manufacture enough under good manufacturing practice so that we can now apply to the FDA to perform clinical trials in patients. We're very excited about this because we think this antibody works differently than other antibodies used in treatment. Often times when you give antibodies to treat patients, they actually tag the leukemia cell or mark it for the immune system and say that cell should be destroyed. This antibody is actually working by affecting the protein that's important for the survival of the leukemia. We think it has a different mechanism of action all together.

It's not just about treating it, it's about killing it?

Dr. Kipps: What we hope to find is the ability to eradicate these cells and eradicate the roots of the leukemia. We're doing a lot of work now in other cancers because one of the fascinating things that we've found is this protein is not just expressed on leukemia, but expressed on a variety of different human cancers. We found it in breast cancer, ovarian cancer, prostate cancer, colorectal cancer, lung cancer, and melanoma. We are very excited about the prospect that it may be a marker for some of these tumors.

We've been hearing about researchers and doctors turning your own immune system against the cancer instead of pumping in toxic drugs. Is this the approach now?

Dr. Kipps: Yes. We're in what's called immune checkpoints. We have to have checkpoints because we have to prevent what's called serious autoimmunity. There are patients who have serious autoimmune diseases and these immune checkpoints can break the immune system so that you don't start reacting to your own cells. In cancer, they can script that process and amplify it so that the immune system has no chance in recognizing the cancer. Now that they're using antibodies that can block those checkpoints, it may run the risk of developing autoimmunity. On the other hand, we might be able to develop immunity against the tumor in patients that are treated with those forms of therapy. We might find other antibodies perhaps like this antibody in patients that are treated. I think we are doing early clinical studies. I think there may be a way that this antibody therapy may be more selective because in binding only the tumor cell, it's not going to affect other cells in the body. We may have a selective approach in going after the cancer. We also have early data now to suggest that this antibody may be effective in preventing the relapse and metastasis of cancer, which I'm very excited about.

Is this a high occurrence for CLL patients?

Dr. Kipps: Unfortunately, at diagnosis, the disease is everywhere. If you did a skin biopsy, a prostate biopsy or a breast biopsy, you will find the CLL cells present and all throughout the body. The leukemia is pretty fastidious and requires a certain constellation of buddy cells, which we call in the micro-environment. It's only there that the leukemia cell can grow. Those are in the lymph nodes and the spleen. So, these are the micro-environments which are like nurseries for the CLL cells. The leukemia can spread everywhere and that is why you just can't cut this out.

Is it just certain people with this certain protein or will it work on everyone?

Dr. Kipps: We found this protein in all patients or most all patients with chronic lymphocytic leukemia. What's exciting to me is that the tumors are less differentiated. The ones that have more primitive effects look almost like they're going back to their embryonic roots. It may not be expressed in all cancers, but we think that there might be elements of cancer cells which express this protein and some patients have a lot of these cells and some patients have few of these cells. It seems to me if you have a lot of these, they go out and germinate other parts of the body and spread even after you've been successful with other forms of treatment.

Is this something that you could tell in utero if it's going to happen?

Dr. Kipps: We sometimes treat cancer like it's an alien from outer space. Cancer is the same cells that we have in our body that mutates or changes, which affect their growth properties or their survival properties. To spread or to germinate to other parts of the body, they may have to rely on programs we saw earlier during embryonic development. Think about it as an embryo… we start out with a group of cells that's just a ball and the cells in that embryo have to metastasize to other parts of the embryos so that they can seed and develop a new organ. It's a good thing if it's embryo geniuses, but it can be a devastating thing if you're a patient with cancer that's trying to go through the same reprogramming process. Hopefully, we can go after those types of programs and have a more generic approach to trying to prevent this from recurring.

How is this research developing?

Dr. Kipps: I'm tremendously grateful to our patients. These patients have taught me a tremendous amount and continue to teach me. I listen to them; I try to understand what they're going through and try to understand the disease that's affecting their lives. From that, we can really learn from them and try to address how to make that better. How do we find clues to circumvent the cancer or to prevent it all together? I've been fortunate to be involved in a number of Phase I studies. First in man studies, and we've also been involved in pivotal studies which have resulted in the registration of four new drugs in the past year. How can we address this cancer, how can we make it more familiar, how can we prevent the ravages of it and not cause a lot of collateral damage. That's been the goal of many cancer researchers. Research has been done through genomic sequencing techniques, biochemistry or cellular biology.

This is one your patients' fourth clinical trial. He says that any drug that just attacks the cancer and not everything else in his body is a good drug. How does that make you feel?

Dr. Kipps: We have to talk about the true heroes in medicine. Those are the patients that volunteer for clinical trials. They are the ones that have courage and fortitude. They have the ability to step out into the unknown. They're taking tremendous risks but they're doing it in the hope that they'll learn something if not to improve their own lives but to improve other people's lives. They're really the heroes today. So, people like Ed Feinberg, my hats off to him, he's my hero.