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.