A Cancer Doctor Weighs In On CAR-T, Precision Medicine And Pricing Debates

Excerpt:

“Yesterday’s historic FDA approval of the first engineered T-cell treatment for cancer, Novartis’ Kymriah (tisagenlecleucel), was accompanied by inevitable questions about how the product would be priced. In the end, Novartis set the price at $475,000, which was lower than many analysts had predicted, considering the treatment is designed to cure some forms of acute lymphoblastic leukemia (ALL)—and in clinical trials it did just that for most patients.”

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Reengineering Immune System Cells to Fight Glioblastoma


Glioblastoma multiforme (GBM) is a diagnosis to fear. The search for better treatments is ongoing, but with little to show since the U.S. Food and Drug Administration (FDA) approved the use of the chemotherapy drug temozolomide with concurrent radiation 12 years ago, based on data showing modest improvement in patients’ survival.

By now, a new cancer treatment approach known as CAR T-cell therapy is famous for its remarkable success in certain blood cancers. But there is not yet much to report for CAR T-cell therapy in solid tumors such as GBM. Still, the treatment may hold promise, and this post will discuss the possible applicability of CAR T-cell therapy in GBM.

What is CAR T-cell therapy?

CAR T-cell (chimeric antigen receptor-engineered T-cell) therapy is based on early work of Israeli scientist Zelig Eshhar conducted in the laboratory of the renowned T-cell treatment pioneer Steven Rosenberg at the National Institutes of Health (NIH). They first prepared CAR T cells to target melanoma, and the treatment has since been shown to work amazingly well in certain types of blood cancer, including B-cell leukemia, and lymphoma. Continue reading…


Reengineering Immune System Cells to Fight Glioblastoma

Glioblastoma multiforme (GBM) is a diagnosis to fear. The search for better treatments is ongoing, but with little to show since the U.S. Food and Drug Administration (FDA) approved the use of the chemotherapy drug temozolomide with concurrent radiation 12 years ago, based on data showing modest improvement in patients’ survival.

By now, a new cancer treatment approach known as CAR T-cell therapy is famous for its remarkable success in certain blood cancers. But there is not yet much to report for CAR T-cell therapy in solid tumors such as GBM. Still, the treatment may hold promise, and this post will discuss the possible applicability of CAR T-cell therapy in GBM.

What is CAR T-cell therapy?

CAR T-cell (chimeric antigen receptor-engineered T-cell) therapy is based on early work of Israeli scientist Zelig Eshhar conducted in the laboratory of the renowned T-cell treatment pioneer Steven Rosenberg at the National Institutes of Health (NIH). They first prepared CAR T cells to target melanoma, and the treatment has since been shown to work amazingly well in certain types of blood cancer, including B-cell leukemia, and lymphoma.

Many improvements in CAR T-cell engineering have been made since its initial development, but the concept remains, in essence, the same: There are many types of immune cells collectively named T cells, but some of them are of the “cytotoxic” variety. Cytotoxic T cells have the useful function of killing cells that possess some proteins (antigens) perceived as foreign, like viral or bacterial proteins. Cancer cells may express some antigens (neoantigens) that are not found on normal cells, and should, in principle, be recognized and killed by cytotoxic T cells. However, this does not always happen because cancers have many different ways to either avoid recognition by T cells, or to inactivate T cells by creating an immune system-suppressing tumor microenvironment.

The general idea behind CAR T-cell therapy is to equip T cells taken from patients’ blood with a specific receptor that recognizes a particular neoantigen on cancer cells. These modified T cells are then infused back into the patient in the hope that they will destroy cancer cells that express that specific neoantigen.

Challenges for CAR T-cell therapy in solid tumors

There are several reasons why the CAR T-cell approach presents a formidable problem when it comes to solid tumors. First, it is difficult to find antigens that are expressed in cancer cells but not in normal tissues. A protein present in a solid tumor is most often also present in normal tissues and organs. To target it with CAR T cells would be really dangerous; normal tissue could be destroyed along with the tumor, without a chance to be replaced (most solid tissues are not continuously renewed like blood cells).

So what about neoantigens or mutated proteins found on cancer cells only? This is a good idea that has so far produced some promising results in tumors that express certain viral proteins, like HPV in cervical cancer. However, a lot of neoantigens do not present good targets for T cells for reasons that have to do with the details of how immune recognition works.

Lack of good targets for CAR T cells is just the first obstacle. The second one is the fact that T cells often cannot travel to tumors due to impaired tumor vasculature (blood vessel arrangement), and/or heavy tumor stroma (non-tumor cells encasing and blocking access to tumor cells). The third problem is that tumors actively develop mechanisms to avoid T-cell attack, like new mutations that prevent antigen presentation and immune recognition. Fourth, even if cytotoxic T cells do manage to infiltrate tumors, cancer cells often express certain proteins that directly inhibit them. Cancers also produce proteins that attract inhibitory immune cells of several types, such as regulatory T cells or myelosuppressive cells. Myelosuppressive cells repel and inhibit cytotoxic T cells, including CAR T-cells that have been infused into the body.

Why GBM?

Due to the known problems described above, few clinical trials are actively developing CAR T-cell strategies for treatment of solid tumors. However, among those that are, GBM seems to be disproportionally represented. This is possibly due to the simple fact that nothing else has really worked in GBM. It is also hoped that GBM may have some “unique” antigens that could be targeted safely.

Current CAR T-cell trials in GBM

Late last year, researchers described a case of successful treatment of a GBM patient with CAR T cells targeting a protein known as IL13Rα2, which is found in GBM cells. The patient, who had several tumors in the brain, received multiple injections of CAR T cells into the cavity left by a resected (surgically removed) tumor, and also into the brain ventricular system to ensure delivery to un-resected tumors. This worked remarkably well for over 7 months, but new tumors unfortunately developed and were successfully treated with more CAR T-cell infusions, this time also into the cerebrospinal fluid. Responses to treatment were also observed in some other patients enrolled in the same ongoing clinical trial, which is run by City of Hope in California (NCT02208362).

Other GBM CAR T-cell trials target EGFRvIII, a particular version of the EGFR protein that is found in GBM. EGFRvIII is not a universal target in GBM because it is expressed in less than a third of patients’ tumors. The other problem is that even if it is found in a given tumor, its presence within that tumor may not be uniform; some (many?) of the cancer cells in a tumor that tests positive for EGFRvIII overall do not have the protein, and will therefore avoid recognition by CAR T cells directed towards EGFRvIII.

Recently published results document these anticipated problems, as well as new problems with EGFRvIII-targeting CAR T cells. In a study conducted at the University of Pennsylvania (NCT02209376), 10 patients with EGFRvIII-positive tumors received one intravenous infusion of CAR T cells targeting EGFRvIII (versus direct injection into the tumor used in the City of Hope trial mentioned above). Seven of the patients had their tumors resected after infusion of CAR T cells, which allowed for analysis of changes induced by the modified T cells. Loss of the EGFRvIII antigen after CAR T-cell treatment was seen in five of the seven resected tumors. This could be due to successful killing of EGFRvIII-positive cells, or it could be the result of loss of EGFRvIII expression by tumor cells.

Unfortunately, CAR T-cell treatment also created an immune system-suppressive environment in the tumors of the treated patients. This manifested as increased expression of some proteins known to dampen immune response (including IDO and PD-L1) and recruitment of cells that inhibit cytotoxic activity of T cells. However, it should be possible to overcome this type of resistance by adding a relevant immune checkpoint drug to CAR T-cell treatment.

One of the 10 patients in this trial was alive at 18 months post-treatment. Overall, these data indicate that CAR T cells infused intravenously do travel to GBM tumors, but also that the tumors employ a variety of mechanisms to repel the immune attack.

At least three more ongoing clinical trials are investigating CAR T cells that target EGFRvIII. Additionally, a new target for CAR T cells in GBM is now being explored: CMV, a virus thought to be associated with and suspected to contribute to development of GBM. One trial (NCT02661282) will administer up to four intravenous infusions of CMV-specific CAR T cells to patients receiving temozolomide.

However, there is a potentially serious problem with CMV-directed CAR T cells: Even though many publications have reported that CMV is found in practically all GBM tumors, a number of publications have failed to confirm this. While some GBM patients are seropositive for CMV antibodies in their blood (meaning that they have been infected with the virus at some point in their lives, as have many healthy people), the potential absence of CMV from tumor tissues may spell failure for CAR T cells targeting CMV. Time will tell.


Combining CAR T Cells With Existing Immunotherapies May Overcome Resistance in Glioblastomas

Excerpt:

“Genetically modified “hunter” T cells successfully migrated to and penetrated a deadly type of brain tumor known as glioblastoma (GBM) in a clinical trial of the new therapy, but the cells triggered an immunosuppressive tumor microenvironment and faced a complex mutational landscape that will need to be overcome to better treat this aggressive cancer, Penn Medicine researchers report in a new study this week in Science Translational Medicine.”

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Results of Glioblastoma Clinical Trial Show Safety and Clinical Benefit of CAR T Cell Therapy

Excerpt:

“Glioblastoma is the most common brain tumor in humans and also one of the most difficult cancers to treat; patients with this type of cancer only survive about one year from time of diagnosis. Researchers at Baylor College of Medicine, Texas Children’s Cancer Center, and the Center for Cell and Gene Therapy at Baylor, Texas Children’s Hospital and Houston Methodist are investigating a new treatment option using modified T cells with anti-tumor properties with the goal of improving outcomes for patients with glioblastoma.

Their research focuses on engineered T cells that target the protein HER 2 expressed in low levels in . Results of a Phase 1 study published in the current issue of JAMA Oncology established the safety of these HER 2-specific, chimeric antigen receptor modified T cells (CAR T cells) when infused in to patients in increasing doses and, importantly, results also showed a clinical benefit to patients.”

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Super ASK Patient: Re-Engineered Blood Cells Successfully Treat Mary Beth’s Relapsed Lymphoma


In early 2016, Mary Beth Smith was getting ready to retire after almost 40 years as a morning radio broadcaster in Toldeo, Ohio. She was an active 62-year-old working mom. She loved walking her two dogs everyday, learning to play pickleball, reading voraciously, spending quality time with her husband—the love of her life for 27 years, and watching their daughter and two sons grow into thriving adults. 

However, her life was quickly interrupted by a relapse of non-Hodgkin’s lymphoma (NHL), which she had first dealt with in 2012. Here, she shares her story.

How were you first diagnosed with non-Hodgkin’s lymphoma?

In November of 2012, I thought I was having an appendicitis issue. A CT scan revealed several swollen lymph nodes in my abdominal cavity—totally unrelated to the appendicitis discomfort; I truly believe the saying, “coincidence is God’s way of remaining anonymous.”

A second CT scan and a surgical biopsy proved the lymph nodes were diffuse large B-cell lymphoma (DLBCL), and I immediately began six treatments of R-CHOP chemo, three weeks apart. Subsequent PET scans showed I was crystal clear of the cancer—and I remained so for two years.

What happened after those two years?

A routine PET scan in 2015 revealed the cancer had returned, but this time in the form of follicular cancer—a much lower grade—and requiring no treatment; just a “watch-and-wait” process which could take many years to manifest itself into anything serious.

In early 2016, the follicular lymphoma had transformed into the diffuse large B-cell, and I was then on track for a more rigorous course of treatment: a stem cell transplant of my own cells. This is not an easy process; it requires harsh chemotherapy and then the transfer of your cells back into your body. Unfortunately, two follow-up PET scans showed the transplant did not work for me.

At that point, you reached out to Cancer Commons. How did you hear about ASK Cancer Commons?

Again, coincidence (God’s way) intervened, and I heard from a friend of many years, Jude LaCava, who had started the Dorothy Foundation in honor of his mother who had died from cancer. He was wondering how I was doing, and when I told him about my latest challenges, he recommended I get in touch with Cancer Commons. Specifically, he said to contact chief scientist Emma Shtivelman who researches all the possible clinical trials available to patients like me.

How has Dr. Shtivelman helped you?

Dr. Shtivelman was a godsend who took me from desperation to hope in a matter of a few emails. She sent me many clinical trial possibilities and particularly focused on a relatively new and still experimental immunotherapy known as CAR T-cell infusions. These infusions use your own white blood cells (T-cells), which are sent to a lab for several weeks to be re-engineered to fight the cancer in your system. In other words, your own blood cells attack the cancer.

I also contacted the Leukemia and Lymphoma Society (LLS) because they also have a nurse navigator who studies clinical trials. She also said CAR T-cell therapy was the latest treatment that seemed to be having encouraging results. When I cross-referenced the material from Cancer Commons and LLS, I came up with several matching clinical trials involving the CAR T-cell treatment. The goal was to find one near my home in Toledo, if I could. And to find one that would accept me sooner than later.

You ended up enrolling in a CAR T-cell trial at Cleveland Clinic last November. How did you decide on that specific trial?

My local oncologist knew the hematologist/oncologist at Cleveland Clinic who was well versed in CAR T-cell treatment. This physician was able to see me reasonably quickly and the next thing I knew, I was #3 on the list to become part of their clinical trail. Within weeks, I had moved up to #1 on the list and the process really accelerated from there.

From November through December 2016, I went through extensive testing required by the Kite pharmaceutical company to determine if I met their criteria for entry into the clinical trial. This included a biopsy of my cancer nodes, a bone marrow biopsy, a lumbar puncture, a heart and lung evaluation, and numerous blood tests to make sure I had no infections, viruses, or any inflammation. When all was said and done, I appeared to be an excellent candidate for this trial. I was reasonably healthy and the cancer was considered a low-burden disease that had not spread beyond my abdominal area.

What was it like to receive CAR T-cell treatment in the trial?

On December 5, 2016, my blood cells were taken from my body via apheresis and immediately shipped to the Kite pharmaceutical lab in California to be re-engineered. On December 27, 2016, after 3 days of pre-conditioning chemo done outpatient, I was admitted to the Cleveland Clinic and at noon my “re-engineered” blood cells were blessed by the hospital chaplain and were infused back into in my body. The process took less than 15 minutes. When it was over, I felt nothing. And I panicked a bit thinking those beefed-up blood cells should be wreaking havoc on my system. For 6 days, absolutely nothing happened. I was convinced it hadn’t worked. And then January 1, 2017, the cytokine storm or cytokine response syndrome kicked in! Happy New Year to me—Happy Hellish New Year to my husband.

For 36 hours I was comatose. My body and mind were in a catatonic state. I felt nothing and remember nothing about it. But my husband has never been so terrified and subsequently suggested to Cleveland Clinic personnel that maybe he could have been better prepared for what the results can be from the “storm.” Unfortunately, because this is a clinical trial, the results can be different for every patient. They try to tell you everything they’ve seen—which is why the consent form is 33 pages long and daunting. But until your loved one is actually going through the storm, you can’t really imagine the response.

Once I came out of the “storm,” my only real symptoms were extreme fatigue and weakness. And after less than two weeks in the hospital, I was able to go home to recover. All I wanted to do was sleep. I wasn’t even interested in eating. Thankfully, my husband was able to use his powers of persuasion to get me to go to physical therapy, and he also kept me well-stocked in bottles of Ensure.

January 23, 2017, we returned to the Cleveland Clinic for a PET scan to see how the T-cells had done. Our doctor walked in and immediately gave us the news: a complete response to the treatment—no sign of cancer. I even made him show me the PET scans side by side just to make sure nothing had been missed. The new PET scan had nothing on it. It was a true miracle that had my husband and I crying and then hugging the doctor and our clinical trial nurse. It was unbelievable! We feel so blessed. And prayers do work!

What comes next?

I will be going back to the Cleveland Clinic for frequent check-ups and blood work. And PET scans will be a part of my regular routine over the next several months/years. And I must admit, the PET scans and waiting for the results still leave me feeling anxious and nervous. This is part of my new normal now. In between, I would just like to get stronger and healthier and enjoy the retirement that started a year ago but got detoured.

What advice would you give to someone who is newly diagnosed?

My best advice: you must be your own health advocate. Ask lots of questions and don’t give up when you don’t get satisfactory answers. Whatever type of cancer you have, contact Cancer Commons and the national organization of your type of cancer, and ask about any clinical trials that might be suitable for you. At the very best, you could be put on a path to your own miracle. Secondly, you could be a pioneer that will help someone else find their own miracle.

***

Super Patients are cancer survivors who learned to be more engaged in their own care. Cancer Commons believes every patient can be a Super Patient or benefit from a Super Caregiver. We hope these stories will provide inspiration and hope for your or your loved one’s own treatment journey.


Clinical Trials Test Treatments for High-Grade Brain Tumors


With a few exceptions, glioblastoma (GBM) remains largely incurable, and the U.S. Food and Drug Administration (FDA) has approved few treatments for the disease. Surgery (when feasible), radiation, and temozolomide are used in most patients. But even if a newly diagnosed tumor can be surgically excised, recurrences are too common.

In this blog post, I simply list some of the new treatments available in clinical trials for GBM and other high-grade brain tumors. Only drugs that have at least some preliminary results of activity are included, and the list is not meant to be fully comprehensive. The interested reader can judge for herself what might be of interest, keeping in mind that no single treatment is suitable or will work for all GBM patients. Continue reading…


Case Report: Adoptive T-Cell Tx Shows Promise in Glioblastoma

Excerpt:

“Treatment with autologous chimeric antigen receptor (CAR)-engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2) is associated with tumor regression in recurrent multifocal glioblastoma, according to a case report published in the Dec. 29 issue of the New England Journal of Medicine.

“Christine E. Brown, Ph.D., from the City of Hope Beckman Research Institute and Medical Center in Duarte, Calif., and colleagues describe their clinical experience with a patient with recurrent multifocal glioblastoma who received CAR-engineered T cells. Over 220 days, multiple infusions of CAR T cells were administered through two intracranial delivery routes: infusions into the resected tumor cavity followed by infusions into the ventricular system.”

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Cells Dripped into the Brain Help Man Fight a Deadly Cancer

Excerpt:

“A man with deadly brain cancer that had spread to his spine saw his tumors shrink and, for a time, completely vanish after a novel treatment to help his immune system attack his disease—another first in this promising field.

“The type of immunotherapy that 50-year-old Richard Grady received already has helped some people with blood cancers such as leukemia. But the way he was given it is new, and may allow its use not just for brain tumors but also other cancers that can spread, such as breast and lung.”

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