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Gene Therapy To Treat Leukemia And Multiple Myeloma: An Update

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Published: Aug 31, 2012 3:25 pm

One of The Myeloma Beacon's most popular news stories of 2011 reported on an important new development in the use of gene therapy to treat blood cancers.

In particular, the article described promising results from a small study using gene therapy to treat patients who have chronic lymphocytic leukemia (CLL), and it looked at how those results might translate into new therapies for multiple myeloma (see related Beacon news).

Since the results of the CLL study were made public last year, follow-up results and additional ongoing studies further indicate that this technique may be an important new treatment option in the future for leukemia as well as myeloma patients.

Thus, researchers are investigating the efficacy and safety of gene therapy for the treatment of multiple myeloma and other blood cancers.

In addition, the investigators leading the CLL study are continuing to administer gene therapy to more CLL patients in order to further assess the effectiveness of this treatment strategy.

“We are continuing these studies in CLL patients and hope to report our updated results at the American Society of Hematology meeting in December,” said Dr. David Porter from the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, one of the lead researchers of the CLL study.

As with myeloma, donor stem cell transplantation is currently the only treatment with the potential to cure CLL. However, most CLL patients who receive a transplant relapse, and there are significant risks and side effects to transplantation.

Last August, Dr. Porter and his colleagues published two research articles that suggested their new approach has the potential to cure leukemia patients like donor stem cell transplantation, but in a safer manner.

In their study, the researchers first collected T-cells (a type of white blood cell) from the study participants.

The T-cells were then infected with a virus designed to genetically alter the T-cells so that they could recognize, attack, and kill leukemia cells. The virus also was designed so that the modified T-cells would be able to reproduce and pass along to later generations of T-cells the ability to recognize and kill leukemia cells.

Once the patients in the study had their T-cells collected and altered, the patients were treated with chemotherapy, and the engineered T-cells were then re-infused into the patients.

Following this procedure, two out of three patients achieved a complete response and remained disease-free after 10 months of follow-up time. Moreover, six months after treatment, the patients still had T-cells that continued to seek out and kill leukemia cells.

The third patient achieved a partial response lasting at least eight months.

In recent correspondence with The Myeloma Beacon, Dr. Porter stated that the two patients continue to remain disease-free two years after receiving treatment.

Gene Therapy With Antibodies To Treat Multiple Myeloma And Other Blood Cancers

An approach similar to the Penn method of using T-cells to treat leukemia is also being studied for the treatment of multiple myeloma. The approach, however, needs to be modified so that the T-cells target myeloma cells.

“I believe this therapy will be applicable to myeloma. The major limitation is identifying a specific target on the myeloma cells that the T-cells can recognize,” said Dr. Porter.

“There is a great deal of research being dedicated to trying to identify unique targets, and I believe this technology holds promise for myeloma,” he added.

In an ongoing Phase 1 study, researchers are investigating the treatment of multiple myeloma, CLL, and non-Hodgkin’s lymphoma using genetically altered T-cells that recognize proteins on the surface of all three types of cancer cells.

A main feature of this study is the use of antibodies along with modified T-cells. According to the researchers, both antibodies and T-cells have been used to treat cancer patients, but individually they have not been strong enough to cure most patients.

In this study, the researchers plan to use an antibody – called a kappa antibody – that recognizes a protein called kappa immunoglobulin on the surface of certain myeloma, leukemia, and lymphoma cells. Specifically, the kappa antibody is modified such that it is joined to the patients’ T-cells and therefore works with the T-cells to attack the cancer cells.

Myeloma patients typically have either kappa immunoglobulin or lambda immunoglobulin on all of their myeloma cells.  Therefore, this approach may work for patients with kappa immunoglobulin on the surface of their cancer cells.  A lambda antibody would be needed for this approach to be useful for patients with lambda immunoglobulin on their myeloma cells.

An important advantage of this approach is that healthy B-cells (a type of immune cell) are better preserved as compared to the Penn approach.

Healthy B-cells, in addition to the cancer cells, are targeted by the modified T-cells used in both this approach as well as the Penn approach.  Half of all B-cells have kappa immunoglobulin on their surface, and half have lambda immunoglobulin.  By attaching the kappa  antibody to the modified T-cells, they will target the cancer cells and about half of the healthy B-cells, whereas, in the Penn study, the modified T-cells destroyed all healthy B-cells as well as cancer cells.

Consequently, the researchers expect that although their technique may require a greater number of T-cell/antibody infusions to eradicate the disease -- due to other differences in the way the T-cells are modified as compared to the Penn study -- it may also produce fewer side effects because a greater number of healthy B-cells will be preserved during treatment.

“We anticipate several doses of T-cells may ultimately need to be given to eradicate the malignancy, a disadvantage compared to the Penn approach, but with the advantage of fewer severe side effects,” said Dr. Malcolm Brenner of the Baylor College of Medicine in Houston and one of the lead researchers of the study.

Dr. Brenner and his colleagues have treated four patients to date, but a longer follow-up time is needed to determine treatment results.

“We have treated four patients in the study with one complete response sustained so far, one stabilization but eventual [disease] progression, one no response, and one too early [to determine response]. [It is] too early to comment on the outcomes [of the therapy],” said Dr. Brenner.

He added that there have not been any significant side effects of the treatment thus far.

In the future, Dr. Brenner and his colleagues hope to start another trial using a lambda antibody that recognizes the lambda immunoglobulin on the surface of myeloma and other blood cancer cells. They also aim to improve the efficacy of modified T-cells, making them better able to combat myeloma.

“We will plan a similar trial with a lambda [antibody] if this study is successful, so we would be able to cover all patients with [myeloma],” said Dr. Brenner.

“We are also developing additional ways of making the T-cells more active, safer, and more resistant to [myeloma cells that escape the immune system],” he added.

Gene Therapy Plus Vaccination To Treat Multiple Myeloma

In two related, ongoing Phase 2 studies, Penn researchers are using modified T-cells in order to improve the outcomes of myeloma patients receiving an autologous stem cell transplant.

In one of the studies, the patients will also receive a myeloma vaccine.

Myeloma vaccines are a recent development and are still being investigated in clinical trials (see related Beacon news).

One type of myeloma vaccine, called a protein vaccine, is made of a protein commonly found on the surface of myeloma cells.  This vaccine is used to stimulate an immune system response against myeloma cells.  The vaccine proteins are first absorbed by specialized cells in the immune system.  Then, after the cells absorb the proteins, they encourage other parts of the immune system to attack and kill myeloma cells with proteins on their surface that match the vaccine protein.

According to researchers, one way to improve the results of an autologous stem cell transplant is to help the body’s immune system recover faster after the transplant. This can be accomplished by re-infusing modified T-cells -- the kind of cells used in the Penn research -- into the patient following the transplant.

Another way to improve outcomes is to induce the immune system to fight against the myeloma cells. This is accomplished by administering a myeloma protein vaccine to the patient following the transplant.

Therefore, researchers are administering modified T-cells, and in one of the studies, the T-cells will be administered in combination with a myeloma vaccine, to improve treatment outcomes of myeloma patients following autologous stem cell transplantation.

Specifically, the researchers are using a myeloma vaccine containing a protein called MAGE-A3, which is found in roughly half of all cases of myeloma.

Along with each vaccination, they are adding an immune system stimulant called Hiltonol (poly-ICLC), which may make the immune system better able to respond to the vaccine.

During both studies, the researchers will also investigate whether long-term treatment with Revlimid (lenalidomide) maintenance therapy following the transplant and T-cell infusion will further combat the myeloma and improve the patients’ responses to the vaccine.

For more information about the ongoing clinical trials, please see the descriptions of the kappa antibody, Revlimid maintenance, and MAGE-A3 studies on the Clinical Trials website.

Photo by kaibara87 on Flickr – some rights reserved.
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One Comment »

  • D'Ann Ybarra said:

    I love it. Beautiful! I love reading about all of the advancements that are taking place. Any type of therapy that has minimal side effects as opposed to chemotherapy is great! I look forward to reading more about the Myeloma Vaccine as well as the modified T-Cell infusion therapy.