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Thu, Jan 3 1:45pm · Mayo Clinic researchers identify new strategies that may improve CAR-T cell therapy in Hematology

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Mayo Clinic researchers have developed two new strategies that may improve the performance of chimeric antigen receptor therapy (CAR-T cell therapy) in treating cancer. They are presenting results of their preclinical research at the 2018 annual meeting of the American Society of Hematology in San Diego.

Reducing toxicity in CAR-T cell therapy

“While CAR-T cell therapy has proven successful in treating certain cancers, severe toxicities have limited its widespread application,” says Rosalie Sterner, an M.D.-Ph.D. student working in the T Cell Engineering Laboratory of Saad Kenderian, M.B. Ch.B., a Mayo Clinic hematologist. Sterner says toxicities associated with CAR-T cell therapy include cytokine release syndrome, in which patients can experience fever, nausea, headache, rash, rapid heartbeat, low blood pressure, and difficulty breathing and neurotoxicity.

Sterner says some patients undergoing CAR-T cell therapy get sick during treatment and require a stay in an ICU. She also notes that deaths related to the side effects of CAR-T cell therapy have been reported. Sterner and her colleagues developed a strategy to reduce the severe toxicities associated with CAR-T cell therapy.

The strategy involves blocking the GM-CSF protein, which is produced by CAR-T cells and other cells using a clinical-grade antibody (lenzilumab).

“When we blocked the GM-CSF protein, we found that we could reduce toxicities in preclinical models, says Sterner. “We also were able to demonstrate that CAR-T cells worked better after the GM-CSF protein was blocked.”

Next, researchers used a gene editing technology, called CRISPR, to generate CAR-T cells that did not secrete the GM-CSF protein. Sterner says these modified CART cells were more effective than regular CAR-T cells.

Based on their findings, the research team is proceeding with a phase II clinical trial of the GM-CSF blocking antibody during CAR-T cell therapy. If the trial results are consistent with earlier findings, the therapy could become a standard of care during CAR-T cell therapy at Mayo Clinic.

This research also is published in Blood.

Improving response rates for CAR-T cell therapy in B cell lymphoma

“In CAR-T cell therapy, physicians remove and modify a patient’s T cells to recognize and fight cancer,” says Reona Sakemura, M.D., Ph.D., a hematologist and a postdoctoral fellow in Dr. Kenderian’s laboratory. “Once modified T cells are reinfused into the patient where they seek out and ultimately kill cancer cells.”

Dr. Sakemura says response rates for CAR-T cell therapy vary by disease. For example, in B cell acute lymphoblastic leukemia, response rates of more 90 percent have been seen, compared to response rates of 10 to 30 percent for treatment with conventional chemotherapy. In other blood cancers, such as lymphoma and chronic lymphocytic leukemia, the response rates for treatment with CAR-T cell therapy remain low.

To improve the effectiveness of CAR-T cell therapy in these cancers, Dr. Sakemura and his colleagues developed a strategy to combine CAR-T cell therapy with a drug that targets a protein called “AXL.” This protein is present on the cancer and within the cancer’s environment. The drug, called “TP-0903,” not only kills cancer cells, but also it enhances the potency of CAR-T cells in attacking cancer cells and potentially lowers the toxicity associated with CAR-T cell treatment.

While more research and clinical trials are needed, Dr. Sakemura says, “We believe the latter effect may eventually be utilized as an innovative approach to augment the efficacy of CAR-T cell therapy and extend its use to other B cell cancers.”

Original story from Mayo Clinic News Network by Joe Dangor

Meet Mayo Clinic Connect members talking about CAR-T treatment in the CAR-T cell Therapy Group

Dec 14, 2018 · Immunotherapy to fight cancer: Dual-immunomodulation in Hematology

Cancer cells have learned and evolved to display a protein on their surface that sends a negative stopping signal to our immune system, halting our immune system from activating and recognizing the cancer cells.

Immunotherapy tries to induce our immune system to recognize and kill the cancer by blocking cancer cells from highjacking that checkpoint mechanism. These drugs are known as checkpoint inhibitors. They act by interfering with the cascade of signals sent by the cancer cell and liberate the immune cells for a successful anti-cancer attack.

Our immune system, especially when faced with cancer cells, can experience what is called immune cell exhaustion. Immune cells become so tired of seeing cancer cells around that they essentially get used to them and give up. This is why introducing only a checkpoint inhibitor will not work. The immune system is still too weak to activate.

What happens when immunotherapy does not work because our immune system is too weak to activate?

Mayo Clinic researchers are combining a checkpoint inhibitor to bypass the negative signal from the cancer cell and another drug to give the immune system a boost to strengthen our response.

“What we are trying to do is to block the signal from the cancer cell, and at the same time give a second positive signal that pushes our immune cells to activate,” says hematologist J. C. Villasboas, M.D. 3704053_0008

“Because we are now trying to modulate two different signals, both the negative (inhibitor) and positive signals, we are calling this therapy a dual-immunomodulatorytherapy.”

According to Dr. Villasboas, this is the first big study where these two drugs are being combined to fight aggressive lymphomas that otherwise have not responded to conventional treatments.

Although the current study is looking specifically at the effectiveness in patients with aggressive B cell non-Hodgkin’s lymphoma, the implications could be vast.

“This study on dual-immunomodulation, if effective, could be a launching point for treating many different types of cancers,” says Dr. Villasboas. “It could be revolutionary in cancer treatment and it is very exciting.”

Meet Mayo Clinic Connect members talking about living with Blood Cancers & Disorders and share your experiences or concerns in the member-to-member support group:

Dec 6, 2018 · Immunotherapy to fight cancer: What is it and how does it work? in Hematology

Let’s start by refreshing our understanding of how our immune system works (in case you can’t recall your high school biology course in perfect detail).

Our immune system fights invaders, such as germs, throughout our body. Another important function of our immune system is to recognize and destroy cancer cells that may form within our body. Our immune system naturally gets weak, or tired, as we age. Additionally, cancer cells can develop an ability to hide from the immune system, or can disable the immune system from acting against them. Combine a tired immune system with a cancer that turns it off (or hides from it), and the result can be particularly troubling for the older population.

The goal of immunotherapy for cancer is to induce our immune system to recognize and kill cancer cells. Over the past few decades, immunotherapy has become an important part of treating some types of cancer.

How our immune system is activated and how cancer cells have found a way around our immune system:

  • When our immune system sees something foreign, it receives a series of signals
    • + Signal 1 – get ready
    • + Signal 2 – confirms threat and activates the immune system to attack
    • – Signal – a negative signal (also known as a checkpoint) is sent to indicate the harmful entity has been controlled and it is time to shut off
  • Cancer cells have evolved to display a protein on their surface that sends the negative signal to the immune system, preventing it from activating and eliminating the cancer cells

Immunotherapy tries to induce our immune system to recognize and kill the cancer cells by introducing a checkpoint inhibitor. Checkpoint inhibitors are drugs that interfere with the cascade of signals sent by the cancer cell to deactivate the immune system.

“What we are trying to do is to block the signal from the cancer cell so that our immune system activates as it normally would,” says hematologist J.C. Villasboas, M.D. 12_6_18_Villasboas

“Immunotherapy has been a homerun for classic Hodgkin’s lymphoma,” says Dr. Villasboas. “But the other 90 percent of lymphomas have had limited activity when treated with checkpoint inhibitors alone.”

Coming up next, we will look in to what happens when checkpoint inhibitors alone are not enough to activate our immune system. Dr. Villasboas and Dr. Stephen Ansell are on the forefront of research in dual-immunomodulation, a technique that combines both checkpoint inhibitors and immune system accelerants. Discover opportunities and learn more about Clinical Trials at Mayo Clinic.

Meet Mayo Clinic Connect members talking about living with Blood Cancers & Disorders and share your experiences or concerns in the member-to-member support group.

Nov 12, 2018 · Donating Bone Marrow & How it is Used in Hematology

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Every year, thousands of people in the U.S. are diagnosed with life-threatening diseases, such as leukemia or lymphoma, for which a stem cell transplant is the best or the only treatment. Donated blood stem cells are needed for these transplants.

November is National Marrow Awareness month.

You might be considering donating blood or bone marrow because someone in your family needs a stem cell transplant and doctors think you might be a match for that person. Or perhaps you want to help someone else — maybe even someone you don’t know — who’s waiting for a stem cell transplant. Learn more about bone marrow donation at Mayo Clinic here.

Meet other Mayo Clinic Connect members talking about living or caring for someone with blood cancer or disorder in the following discussions:

Oct 22, 2018 · Multiple Myeloma: Patients and caregivers support meeting in Hematology

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Ilse Hein was diagnosed with multiple myeloma during a hospitalization for pneumonia in 1992 in her hometown of Barrington, Illinois. Encouraged by her local physicians, Ilse traveled to Rochester, Minnesota, and spent a week at Mayo Clinic.

After years of surveillance at Mayo Clinic, Ilse’s team of physicians recommended she participate in a new drug trial. Fortunately, Ilse’s multiple myeloma improved as a result of the trial. It was at that time she decided it was time to help other multiple myeloma patients.

As a myeloma patient advocate, @ilse worked hard to start a new project called Multiple Myeloma Mayo Mentorship, a face-to-face patient program, in addition to Mayo Clinic Connect, she hopes will give incoming patients added support with someone who has been in the same spot. 

“My goal is to give patients and caregivers information, hope, courage, understanding, and to provide emotional support,” Ilse says.

Ilse’s support group meets for the first time on Tuesday, November 6, 2018 and is open to anyone who has multiple myeloma or caregivers of those who have multiple myeloma. Additional details:

  • When: Tuesday, November 6, 2018
  • Where: Mayo Clinic Rochester – Gonda building, 10th floor room 160.
  • Time: 5pm to 6pm CT

Sign up for event reminders here.

“Choose a knowledgeable cancer team and specialist you trust and connect with. I wholeheartedly recommend Mayo Clinic. You will need your family, friends and your cancer team to be on your side through your cancer journey. Seek support from others, and never ever give up,” Ilse says.

In addition to Ilse’s support group, join Connect members discussing the diagnosis, treatment, and living with multiple myeloma:

Oct 15, 2018 · Young Cancer Patient Finds Answers (and “Rainbows”) at Mayo Clinic in Hematology

10_15_18 Alley Downing

Alley Downing was marking a milestone. She’d finished her last chemotherapy treatment, and to celebrate, she got a crown: a beautiful henna design that rested where her hair had been just months earlier.

The whirlwind journey to that royal ending started in April, when Alley began to feel tired. Really tired. Then she came home from track day at her school and told her mother, Tamra, that it hurt to take a breath. A trip to urgent care suggested inflammation of Alley’s trachea, but the medication she was prescribed didn’t help, and soon Alley was experiencing additional symptoms. She had migraines. Dizziness. Low blood pressure. More doctor appointments led to more medications, but no resolution. When Alley discovered an enlarged lymph node above her collar bone, her mother – who’d worked as a nurse and physician assistant before her children were born — started to panic.

“My alarm bells went off like crazy,” Tamra tells us. By this time, Alley was also having fevers and night sweats, and had lost five pounds in just a week. Yet doctors near the family’s Chicago-area home insisted Alley’s symptoms were likely related to a virus.

“I was feeling desperate,” Tamra says. “I felt it in my bones that something was wrong. My daughter felt it in her bones that something was wrong. But the whole time, no one was listening.”

That changed in early June, when Tamra brought Alley to Mayo Clinic’s Rochester campus. Within three days, doctors had a preliminary diagnosis: Hodgkin’s lymphoma. “At Mayo Clinic, I finally had doctors who listened to me and took my concerns seriously,” Tamra says. “I was so thankful we came up here.” Additional testing confirmed the diagnosis, and pediatric hematologist/oncologist Vilmarie Rodriguez, M.D., laid out a plan for treatment, which included surgery and chemotherapy.

Treatment wasn’t easy. Chemotherapy often left Alley feeling exhausted and nauseated. But there were bright spots along the way. One of them was Brighter Tomorrows, a nonprofit organization that supports families affected by childhood cancer. Another “cancer mom” invited Tamra and Alley to one of the group’s monthly meetings. “Alley wasn’t feeling well, so I told her we’d only stay for five minutes,” Tamra says. “We brought her in in a wheelchair. She felt horrible. She was sad. She was shy. But a group of girls came up to her like they’d known her forever. They were so encouraging to her, so loving to her. By the end of the night she was out of the wheelchair, having fun and making friends. She had a smile on her face.”

Tamra says she “fell in love” with Brighter Tomorrows that night. “It has been a godsend to me,” she says. “The people there have walked in our shoes. The support the organization gives is unbelievable.”

Also unbelievable, Tamra says, is Mayo Clinic, from the care providers who listen, to the art and music therapy programs that also put smiles on Alley’s face. (You can see that smile — and hear Alley sing — in this video). “Throughout this experience, there have been rainbows,” Tamra tells us. “It’s been a horrible experience, but a beautiful one.”

It’s an experience that continues. “Treatment is over and we’re so happy about that, but it’s not like this ends for her,” Tamra says. Alley still has side effects from treatment, including significant pain and weakness in her legs. Since chemotherapy can affect fertility, Alley may have difficulty someday becoming pregnant, and she had one of her ovaries removed and preserved in case she does. And though test results show she’s now cancer-free, Alley will need to be monitored for the rest of her life to make sure that remains the case. “Cancer is devastating for anybody,” Tamra says. “But when you’re 14, or 4, or 4 months, it’s a completely different thing.”

That’s something that has changed Alley’s perspective on life. “I feel like every day you should be thankful,” she tells us. “Live every day like it’s your last.”

You can see Alley’s art, including work she created during her treatment, here.

Meet others talking about living with Lymphoma on Connect

Read more patient stories on Mayo Clinic’s In the Loop

Sep 25, 2018 · Chimeric antigen receptor T cell therapy (CAR-T cell therapy): How it works and what is next in Hematology

Dr. Yi Lin, chair of the Cellular Therapeutics Cross-Disciplinary Group at the Mayo Clinic Cancer Center, explains how chimeric antigen receptor T cell therapy (CAR-T cell therapy) works and where the research is headed next.

Learn more about the basics of the breakthrough cancer treatment and where the research is heading next.

Connect with real members discussing their diagnoses in the Blood Cancers & Disorders group, as well as the CAR-T Cell Therapy group.

Lin, Yi M.D.

Sep 20, 2018 · Bone Marrow Transplant and CAR-T Cell Therapy Q&A in Hematology

Learn more about bone marrow transplants (BMT) and CAR-T therapy with Mohamed A. Kharfan Dabaja, M.D., M.B.A. Dr. Kharfan-Dabaja gives an overview of treatment options and then fields questions from Mayo Clinic Connect and Facebook members.

Bone marrow transplants are now also known as hematopoietic stem cell transplants. There are two types of hematopoietic (BMT) transplants, autologous and allogeneic.

An autologous transplantation is when a patient uses cells from their own body. The process for autologous transplantation is as follows:

  • Patient is given what are called growth factors to stimulate the bone marrow to expand the stem cell pool (4 to 5 days)
  • Patient is connected to an apheresis machine to remove the stem cells (usually 4 to 6 hours but can be longer)
  • After stem cells are administered, patient must stay near a Mayo Clinic facility for an average of 7-14 days for follow up

Allogeneic transplantation uses cells from a donor — typically a matched related donor such as a child or parent. The process for an allogeneic transplantation is as follows:

  • First, a suitable HLA (human leukocyte antigen) compatible donor match must be found
  • The donor must then be tested for any communicable diseases, as well as undergo a physical to ensure the donor is able to handle the procedure as well
  • The patient will undergo conditioning chemotherapy
  • After stem cells are administered, patients must stay near a Mayo Clinic facility for an average of 2 to 2 ½ months

Follow up appointments for each transplantation monitor for recovery and assessments of the disease. Also, appointments will monitor for infections due to the lowered immune systems because of the procedure itself.

CAR-T cell Therapy (chimeric antigen receptor T-cell)

3D-illustration-of-CAR-T-cell--eaf6d313-f954-48bb-ace4-b6ee2a068434-1602651669_pOur bodies contain cells, in this case T lymphocytes, that fight against infections and against cancer. Sometimes, those cells do not function properly or they do not recognize cancer cells. In short, CAR-T therapy isthe re-engineering of your T-cell lymphocytes:

  • Cells are taken from the patient
  • Cells are processed, or manufactured, by introducing cells that are present on the cancer cells
  • Cells are then reinfused in the patient

Patients must meet specific criteria for approved disease that qualify for CAR-T therapy, as well as physical exams to determine the patient can handle CAR-T therapy.

Tune in to the 8:30 minute mark of the video to watch Dr. Kharfan-Dabaja answer questions from Connect and Facebook members.

Click here or more information on CAR-T-cell therapy at Mayo Clinic or to request an appointment.