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ASH 2013 Preview: Novel Immunotherapies Under Development For The Treatment Of Multiple Myeloma

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Published: Nov 23, 2013 9:04 am

As The Beacon continues its ‘ASH Preview’ series about myeloma re­search that will be presented at the American Society of Hematology (ASH) meeting in early December, this article focuses on novel im­muno­therapy approaches that are being studied in clinical trials.

Abstracts for the ASH presentations are now available, although many contain pre­lim­i­nary information that will be updated at the meet­ing.

The Beacon’s ASH preview articles are intended to highlight the meet­ing’s most interesting myeloma-related studies.

The first several of the preview articles, which were published over the past week, provide an overview of ASH abstracts about potential anti-mye­lo­ma drugs that are in clinical development.

Today’s preview continues with the theme of new therapies being developed for myeloma, but this article turns its attention to novel immunotherapies that are in clinical development.

Immunotherapies are treatments that activate, train, or modify the body’s immune system to attack and kill myeloma cells.

This article discusses immunotherapies that involve vaccination or modification of immune cells, often in com­bi­na­tion with stem cell trans­plan­ta­tion using stem cells either from the patient or a donor.

The potential use of monoclonal antibodies to treat myeloma – another form of immunotherapy – has been discussed in earlier ASH preview articles

Several of the studies in this preview show early promise.  In the first two studies discussed below, for ex­ample, 100 percent of the patients responded to treatment.  The result is particularly impressive in the case of the second study, which involved patients who had received several prior therapies.

At the same time, some caution is in order when it comes to drawing conclusions from these studies.

All of the studies are either Phase 1 or Phase 2 trials, which means these approaches are still in the early stages of clinical development and have often only been tested in a small number of myeloma patients.

Also, most of the abstracts provide little detail about the characteristics of the study participants.  For instance, many of the abstracts do not state how early or far into the course of their disease the participants are.  This information is critical to put into perspective how these approaches compare to current treatment options; response rates and survival times are expected to be much greater for newly diagnosed patients compared to those who have been heavily pretreated and are further along the course of their disease.

However, several of these approaches appear to be successful in treating other types of blood cancers, and hopefully these approaches will be as successful for multiple myeloma.  For example, two patients with chronic lymphocytic leukemia who were treated with genetically modified T cells – a type of infection-fighting white blood cell – remained disease free two years after treatment (see related Beacon news).

Therefore, The Beacon will continue to follow these new immunotherapy approaches for myeloma with interest and will update readers with additional details and results presented at the meeting.

MAGE-A3 Immunotherapy, Transplantation, And Lymphocyte Infusion

One Phase 1 study to be presented at ASH is testing a combination of MAGE-A3 immunotherapy, stem cell trans­plan­ta­tion, and lymphocyte infusions (abstract).

In this study, researchers attempted to immunize myeloma patients against a protein called MAGE-A3, which is found on the surfaces of a number of different types of cancer cells, including multiple myeloma cells.  Immunization against MAGE-A3 helps train the immune system to recognize, attack, and kill cells with MAGE-A3 on their surface.

Patients with MAGE-A3 on the surface of their myeloma cells received an initial MAGE-A3 immunotherapy injection in the muscle.  Three weeks later, the patients’ lymphocytes were collected.  Patients then under­went stem cell trans­plan­ta­tion and infusion of their previously collected lymphocytes, followed by seven more MAGE-A3 injections throughout the nine months following trans­plan­ta­tion.  Patients were allowed to receive Revlimid (lenalidomide) maintenance therapy.

The study includes 13 patients who had been diagnosed with myeloma within the last year and had MAGE-A3 on their myeloma cells.  A third of all potential trial participants were found to have MAGE-A3 present on their myeloma cells.

Among the 12 study participants evaluated for response, 83 percent developed antibodies against MAGE-A3 within 31 days of stem cell trans­plan­ta­tion and all developed antibodies within 75 days.  At three months post-transplant, 33 percent of patients achieved a stringent complete response and an additional 17 percent achieved a complete response.  The overall response rate was 100 percent.  At a median follow-up time of 10 months, the progression-free survival rate was 92 percent.

Common side effects included injection site pain, muscle aches, or brief flu-like symptoms.  The in­ves­ti­ga­tors reported one immunotherapy-related case of moderate muscle pain and that the lymphocyte infusions were well tolerated.

Stem Cell Transplantation, Genetically Modified T Cells, And Revlimid Maintenance

A Phase 2 study to be presented at ASH is testing a combination of stem cell trans­plan­ta­tion, genetically modified T cells, and Revlimid maintenance therapy (abstract).

The study participants’ T cells were collected and then infected with a virus designed to genetically alter the T cells so that they recognize, attack, and kill myeloma cells that have the proteins NY-ESO-1 or LAGE-1 on their surface. Two days after undergoing stem cell trans­plan­ta­tion, patients received an infusion of their own genetically modified T cells.  Patients began Revlimid maintenance therapy three months after trans­plan­ta­tion.

This study includes 20 high-risk or relapsed myeloma patients whose myeloma cells have NY-ESO-1 or LAGE-1 proteins on their surface.  They had received a median of 3 prior therapies.  All 15 patients evaluated for response had responded within 100 days after trans­plan­ta­tion, with 13 percent achieving a complete or stringent complete response, 67 percent a near complete response, and 20 percent a partial response.  The modified T cells expanded and persisted in the blood and bone marrow six months after infusion.  Disease progression was accompanied by loss of modified T cells or loss of NY-ESO-1/LAGE-1 on their myeloma cells.  At a median follow-up time of around one year, 85 percent of patients are still alive.

Chemotherapy Plus Genetically Modified Donor T Cells Following Donor Stem Cell Transplantation

A Phase 1/2 study of patients who previously underwent allogeneic (donor) stem cell trans­plan­ta­tion is trying to improve management of disease relapse while minimizing complications through the use of chemo­ther­a­py followed by an infusion of donor T cells that have been genetically modified (abstract).  T cells are a type of white blood cell, known as a lymphocyte, that is part of the body's immune system.

One of the most serious complications of donor stem cell trans­plan­ta­tion is graft-versus-host disease (GVHD), a condition in which donor T cells attack the recipient’s healthy cells.  At the same time, donor T cells also attack and kill residual myeloma cells in a process known as the graft-versus-myeloma effect -- a key objective of donor trans­plan­ta­tion.  Therefore, a balance between the graft-versus-myeloma effect and GVHD is necessary.

In this study, participants who had undergone a donor transplant and were beginning to relapse were treated with cyclophosphamide (Cytoxan) and fludarabine (Fludara) to prepare and boost an infusion of modified donor T cells. The modification of the donor T cells was done with a version of the herpes virus that genetically alters the T cells to make them susceptible to treatment with the commonly-used antiviral drug ganciclovir.

The infusion of the donor T cells induce the graft-versus-myeloma effect; however, if symptoms of GVHD appear, the T cells can be killed with ganciclovir.

The study included 10 patients, 5 of whom had relapsed myeloma and 5 of whom had myelodysplastic syndromes.  Overall, 30 percent of the patients developed acute GVHD after infusions of the modified donor T cells; one case resolved with steroid creams and one case resolved after ganciclovir treatment, but one case did not fully resolve after ganciclovir treatment and required additional immunosuppressive therapy.  Among the patients who did not require ganciclovir, modified donor T cells could still be detected at least 12 months after infusion.  With a median follow-up time of 22 months, the progression-free survival was 50 percent and the overall survival rate was 60 percent.

Modified T Cells Followed By Stem Cell Transplantation

Another Phase 1 study to be presented at ASH this year tested whether infusion of modified T cells prior to stem cell trans­plan­ta­tion creates an immune response against myeloma cells (abstract).

The study included 12 myeloma patients who had received initial treatment after diagnosis.  Researchers then collect the patients’ T cells and attached an antibody to the surface of the T cells.  This antibody helps T cells recognize, attack, and kill myeloma cells that have a protein called CD20 on their surface.  After re­ceiving two infusions of their modified T cells, patients underwent high-dose chemotherapy and stem cell trans­plan­ta­tion.  Some of the patients received a booster infusion of T cells after trans­plan­ta­tion.

The patients had detectable levels of antibodies against myeloma 6 to 12 months after stem cell trans­plan­ta­tion; a booster infusion further increased antibody levels.

Regulatory T Cell Depleted Stem Cell Transplantation

A pilot study of standard autologous (own) stem cell trans­plan­ta­tion compared to autologous trans­plan­ta­tion in which regulatory T cells are removed from the stem cells will be presented at ASH (abstract).

Regulatory T cells, often abbreviated as Treg cells, suppress the immune system from attacking and destroying cancer cells.  Therefore, the researchers in­ves­ti­gated two methods of reducing regulatory T cell levels, also known as T cell depletion, from a patient's own stem cells.

To determine whether depletion of regulatory T cells is feasible, study participants were divided into three different groups: four patients underwent standard trans­plan­ta­tion using their own stem cells, two patients underwent standard stem cell trans­plan­ta­tion and then had their regulatory T cells removed via treatment of the patients with an antibody called Simulect (basiliximab), and three patients underwent trans­plan­ta­tion using stem cells that had regulatory T cells removed in the laboratory prior to trans­plan­ta­tion.

At 28 days after trans­plan­ta­tion, patients in the three treatment groups had an average of 8.6 percent, 4.5 percent, and 1.8 percent regulatory T cells, respectively.  Also, the laboratory-based approach to removing regulatory T cells was found to be able to remove an average of 90 percent of regulatory T cells from the patients' collected stem cells.

The researchers state that both methods of regulatory T cell removal may be effective and side effects in all three treatment groups were typical of stem cell transplantation.  However, they also state that the number of study participants in this pilot study is too small to determine whether regulatory T cell removal has a pos­i­tive impact on patient outcomes.

ImMucin Vaccine

Another Phase 1/2 study that will be presented at ASH is testing a myeloma vaccine called ImMucin (abstract).

ImMucin is a myeloma vaccine that is based on the protein MUC1, which is found on the surface of cancer cells.  ImMucin is being developed by Vaxil Biotherapeutics, an Israeli vaccine development company.

The study included 15 myeloma patients who had received a median of two prior lines of therapy and who had residual or progressive disease following stem cell transplantation.  All participants had myeloma cells with the protein MUC1 on the surface.

Study participants received six or 12 bi-weekly ImMucin injections plus a growth factor known as hGM-CSF.

Patients achieved vaccine-specific immune responses and significant reductions in MUC1 levels in their blood. The majority of patients also achieved disease stabilization that has lasted up to 29 months post study completion.  The study investigators state that the ImMucin vaccine was safe and did not cause any severe side effects.

For information about additional studies that will be presented at ASH, see a list of all myeloma-related ASH abstracts, all abstracts about new treatments under development for myeloma, clinical trial results for new treatments, and preclinical research about new treatments.

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3 Comments »

  • nancy shamanna said:

    Thanks for this interesting article! Just looking at the abstracts for the MAGE-a3 treatment, and also for the ImMucine vaccine treatment, it seems that these methods could be achievable in a widespread way! The MAGE-a3 authors refer to an 'off the shelf' product, which was combined with the first ASCT for patients. The ImMucine vaccine was developed to be used on its own, without having an ASCT transplant. And the vaccine was accepted by the patients' immune systems to achieve a response. That seems good to me since the immune compromised system doesn't always 'take' to vaccines.

  • Eric said:

    ImMucine vaccine looks really promising. No significant side effects and disease stabilization for at least 29 months, wow. Where do we sign up?

  • Annamaria said:

    This article is interesting, altough rather technical. Does anyone know of more articles on the subject? How would this cure work, what would the patient have to do? Is this type of approach expected to be taken by the hemathologists soon, or are we still far from the use of immunotherapy?