What It Is
Immunotherapy is the manipulation of the immune system in order to prevent or treat a disease. One of the most well known examples of immunotherapy is the use of vaccines to prevent infectious disease. However, in the case of myeloma, immunotherapy is being investigated as a means to treat the cancer. Unlike traditional therapies for myeloma, which act directly on the tumor cells, immunotherapy is designed to help a patient's immune system attack the myeloma.
Immunotherapy is an experimental treatment strategy for myeloma. Strategies to harness the powerful immune system are mainly at the pre-clinical stage of development for myeloma, but they are moving toward clinical testing. There is wide variety in the techniques used and the outcomes achieved so far.
Immunotherapy is an experimental treatment strategy for myeloma. Strategies to harness the powerful immune system are mainly at the pre-clinical stage of development for myeloma, but they are moving toward clinical testing. There is wide variety in the techniques used and the outcomes achieved so far.
How It Works
The body's immune system works to defend it against disease and infection. Typically, when a cancer cell arises in the body, the body's immune system recognizes it as abnormal and destroys it before it can spread. However, in some instances and for reasons not yet clear, the body may not recognize the cancer cell and it continues to grow.
In myeloma, patients often do not mount a strong immune response against their myeloma cells. The goal of using immunotherapy is to either help the body elicit an "active" immune response to attack myeloma cells (active immunotherapy) or to substitute an alternative "passive" response prepared outside the body and administered to the patient (passive immunotherapy).
Immunotherapy is likely to be most effective when the number of myeloma cells in the body has been minimized, such as after high-dose chemotherapy and stem cell transplantation. Immunotherapy seeks to destroy the remaining cells, which are thought to responsible for relapse after therapy. However, immunotherapy may also have other indirect anti-myeloma effects, such as:
In myeloma, patients often do not mount a strong immune response against their myeloma cells. The goal of using immunotherapy is to either help the body elicit an "active" immune response to attack myeloma cells (active immunotherapy) or to substitute an alternative "passive" response prepared outside the body and administered to the patient (passive immunotherapy).
Immunotherapy is likely to be most effective when the number of myeloma cells in the body has been minimized, such as after high-dose chemotherapy and stem cell transplantation. Immunotherapy seeks to destroy the remaining cells, which are thought to responsible for relapse after therapy. However, immunotherapy may also have other indirect anti-myeloma effects, such as:
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slowing myeloma cell growth,
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making myeloma cells more vulnerable to destruction by other therapies, or
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affecting the bone marrow microenvironment to make it less hospitable to myeloma cell growth.
Immunotherapy is an active area of research in myeloma. In addition to vaccines, other types of immunotherapy being investigated in myeloma include cytokines and monoclonal antibodies, as well as manipulation of immune cells. Researchers are also investigating new targets and strategies for immunotherapy, as well as working toward a better understanding of the immune defects present in patients with myeloma in order to improve on these strategies.
The sections that follow describe the various types of immunotherapy under investigation in myeloma.
The sections that follow describe the various types of immunotherapy under investigation in myeloma.
Myeloma Vaccines
Vaccines are being developed to treat myeloma rather than prevent it. Several of the vaccines being investigated in myeloma are active vaccines. These vaccines are created using the patient's own myeloma cells or proteins unique to the myeloma cell (also known as antigens). They are usually combined with a stimulus or adjuvant that increases the body's own immune response. The patient is then immunized with this myeloma vaccine to stimulate his or her immune system to fight the disease (see figure below). Because vaccines are targeted to the tumor cells, they have the potential to be more specific and less toxic to the patient than conventional therapies.
Vaccines are created using part of the patient's own myeloma cells. Cells, proteins, or other materials are removed and chemically modified, and often mixed with substances that increase the body's own immune response. The modified substance is then infused to help the patient's own body fight the disease.
There are many types of myeloma vaccines being investigated, including:
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Idiotype protein vaccines
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Dendritic cell vaccines
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Cellular vaccines
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DNA vaccines
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Gene-modified vaccines
Idiotype Protein Vaccines
Idiotypes, the unique portions of a patient's monoclonal protein, offer a unique target for vaccination because each idiotype is unique to a patient's myeloma. A number of studies have investigated the administration of idiotype protein vaccines to patients with minimal disease following autologous stem cell transplant. Because immune responses against idiotypes are often weak, patient-specific idiotypes are often administered with an adjuvant such as KLH. This strategy elicits specific immune responses against the myeloma, and some studies have hinted of responses or a survival benefit, but typically idiotype protein vaccines do not eliminate the residual myeloma cells.
There is much research being conducted to optimize and harness the anti-tumor effect of idiotype vaccines. Techniques to improve idiotype vaccine delivery and performance are being developed. One approach being investigated as a means to increase immune responses against idiotypes is by combining them with dendritic cells (see below). Another strategy based on new developments in genomics is to deliver the idiotype via DNA vaccines (see below). Genetic technology can also generate alternative protein delivery systems such as vaccibodies, which are engineered antibody-like molecules that contain idiotype gene sequences. These molecules have been shown to induce strong antibody and T-cell immune responses in a mouse model of myeloma. (Brunsvik et al. Hematol J. 2003;4(suppl 1):S86. Abstract P13.5.)
There is much research being conducted to optimize and harness the anti-tumor effect of idiotype vaccines. Techniques to improve idiotype vaccine delivery and performance are being developed. One approach being investigated as a means to increase immune responses against idiotypes is by combining them with dendritic cells (see below). Another strategy based on new developments in genomics is to deliver the idiotype via DNA vaccines (see below). Genetic technology can also generate alternative protein delivery systems such as vaccibodies, which are engineered antibody-like molecules that contain idiotype gene sequences. These molecules have been shown to induce strong antibody and T-cell immune responses in a mouse model of myeloma. (Brunsvik et al. Hematol J. 2003;4(suppl 1):S86. Abstract P13.5.)
Dendritic Cell Vaccines
Dendritic cell vaccines utilize dendritic cells, immune cells that play an important role in initiating and regulating immune responses. These vaccines contain dendritic cells that are combined with myeloma idiotypes, other myeloma proteins, or stimulatory compounds, or are fused with entire myeloma cells. It is thought that these cells can help elicit strong anti-myeloma responses. Preliminary results with this strategy are encouraging.
Mylovenge®. One example of a dendritic cell vaccine is Mylovenge® (APC8020i, Dendreon), which is no longer being investigated for use in myeloma. This vaccine used the patient's own dendritic cells that were loaded with his or her specific idiotype. Final results of a Phase I/II clinical trial of the agent in patients with advanced refractory myeloma (n=42) were reported at the IXth International Workshop in Myeloma in 2003. (MacKenzie et al. Hematol J. 2003;4(suppl 1):S270. Abstract 409.) The autologous dendritic cell vaccine appeared to be safe and well tolerated, with adverse events occurring in 10 of the 134 infusions; two episodes of shortness of breath were severe in nature. Treatment induced idiotype-specific T-cell immune responses in 43% of patients that correlated with improved time to disease progression. A small number of these heavily pretreated patients had minor responses or stable disease. It is expected that this type of vaccine may be more effective in patients with lower tumor burden.
Dendritic cell-myeloma fusion vaccines. Vaccination with dendritic cells fused with myeloma cells has been shown to induce specific immunity in animal models. An early clinical study in patients with clinically stable disease shows that dendritic cell-myeloma fusion cells can induce tumor-specific immunity. (Avigan et al. Blood. 2004;104. Abstract 751.) The effect of vaccination on clinical markers of disease is being monitored.
KRN7000. KRN7000 (alpha-Gal-Cer, Kirin Brewery Co.) is a compound with anti-tumor effects that stimulates dendritic cells and other immune cells. KRN7000 is being evaluated in a Phase I trial in combination with a patient's own dendritic cells as a vaccine.
Investigation in Smoldering Myeloma. Preliminary results presented by researchers at the University of Arkansas at the American Society of Hematology (ASH) meeting in 2003 suggest that strong anti-myeloma responses can be generated using dendritic cell vaccination. (Szmania et al. Blood. 2003;102(11). Abstract 1652; Yi et al. Blood. 2003;102(11). Abstract 5277.) These researchers are evaluating this vaccination technique in patients with smoldering myeloma, where strong and long-lasting immune responses were generated. The dendritic cells, which were loaded with patient idiotype, and an adjuvant were injected directly into the patient's lymph nodes, followed by a low dose of the cytokine interleukin-2. Longer follow-up will be needed to determine whether there is clinical benefit.
Use in Combination with Tandem Transplant. Dendritic cell vaccines are also being evaluated at the University of Arkansas in myeloma patients at other stages of disease, including those with poor prognosis myeloma, where vaccination is combined with intensive chemotherapy and tandem autologous stem cell transplantation. In this case, the dendritic cells are collected prior to chemotherapy and are loaded with myeloma cell extracts or idiotype before being frozen and stored. Following the transplant, the thawed dendritic cells are injected directly into the patient's lymph nodes. Patients also receive additional vaccination to boost the response. Preliminary results indicate that this technique results in a rapid increase in T cells that react against the patient's myeloma cells. (Szmania et al. Blood. 2004;104. Abstract 2920.)
Mylovenge®. One example of a dendritic cell vaccine is Mylovenge® (APC8020i, Dendreon), which is no longer being investigated for use in myeloma. This vaccine used the patient's own dendritic cells that were loaded with his or her specific idiotype. Final results of a Phase I/II clinical trial of the agent in patients with advanced refractory myeloma (n=42) were reported at the IXth International Workshop in Myeloma in 2003. (MacKenzie et al. Hematol J. 2003;4(suppl 1):S270. Abstract 409.) The autologous dendritic cell vaccine appeared to be safe and well tolerated, with adverse events occurring in 10 of the 134 infusions; two episodes of shortness of breath were severe in nature. Treatment induced idiotype-specific T-cell immune responses in 43% of patients that correlated with improved time to disease progression. A small number of these heavily pretreated patients had minor responses or stable disease. It is expected that this type of vaccine may be more effective in patients with lower tumor burden.
Dendritic cell-myeloma fusion vaccines. Vaccination with dendritic cells fused with myeloma cells has been shown to induce specific immunity in animal models. An early clinical study in patients with clinically stable disease shows that dendritic cell-myeloma fusion cells can induce tumor-specific immunity. (Avigan et al. Blood. 2004;104. Abstract 751.) The effect of vaccination on clinical markers of disease is being monitored.
KRN7000. KRN7000 (alpha-Gal-Cer, Kirin Brewery Co.) is a compound with anti-tumor effects that stimulates dendritic cells and other immune cells. KRN7000 is being evaluated in a Phase I trial in combination with a patient's own dendritic cells as a vaccine.
Investigation in Smoldering Myeloma. Preliminary results presented by researchers at the University of Arkansas at the American Society of Hematology (ASH) meeting in 2003 suggest that strong anti-myeloma responses can be generated using dendritic cell vaccination. (Szmania et al. Blood. 2003;102(11). Abstract 1652; Yi et al. Blood. 2003;102(11). Abstract 5277.) These researchers are evaluating this vaccination technique in patients with smoldering myeloma, where strong and long-lasting immune responses were generated. The dendritic cells, which were loaded with patient idiotype, and an adjuvant were injected directly into the patient's lymph nodes, followed by a low dose of the cytokine interleukin-2. Longer follow-up will be needed to determine whether there is clinical benefit.
Use in Combination with Tandem Transplant. Dendritic cell vaccines are also being evaluated at the University of Arkansas in myeloma patients at other stages of disease, including those with poor prognosis myeloma, where vaccination is combined with intensive chemotherapy and tandem autologous stem cell transplantation. In this case, the dendritic cells are collected prior to chemotherapy and are loaded with myeloma cell extracts or idiotype before being frozen and stored. Following the transplant, the thawed dendritic cells are injected directly into the patient's lymph nodes. Patients also receive additional vaccination to boost the response. Preliminary results indicate that this technique results in a rapid increase in T cells that react against the patient's myeloma cells. (Szmania et al. Blood. 2004;104. Abstract 2920.)
Cellular Vaccines
Cellular vaccines utilize the patient's myeloma cells to stimulate an immune response.
Gvax® Myeloma Vaccine. One such vaccine combines a patient's irradiated myeloma cells with Gvax® Myeloma Vaccine (Cell Genesys). Gvax consists of cells that secrete a cytokine known as granulocyte-macrophage colony-stimulating factor (GM-CSF), which stimulates immune responses to vaccines. A Phase I/II trial was conducted to see whether Gvax, administered before and after autologous stem cell transplantation, can stimulate an immune response against the myeloma cells and enhance the response induced by high-dose chemotherapy and stem cell transplantation.
Preliminary results from this study were reported at the American Society of Hematology (ASH) meeting in 2004. (Borrello et al. Blood. 2004;104(11). Abstract 440.) At that time, myeloma cells had been harvested from 22 patients; 18 patients had received the pre-transplant vaccination and 16 had received eight post-transplant vaccinations administered at 3-week intervals starting at 6 weeks post-transplant. Of the 16 patients who had received a transplant, there were 6 complete and 5 partial remissions, for an overall response rate of 69%. Three patients with rising M protein levels early post-transplant had decreased M protein levels following the initiation of post-transplant vaccination, suggesting a possible vaccine-medicated effect. No severe (Grade 3 or Grade 4) vaccine-related toxicities have been observed. Local vaccine injection site reactions were seen in all patients but delayed reactions were infrequent (4 of 10 at 1-year post-transplant).
Despite these encouraging results, Cell Genesys discontinued the Gvax myeloma program in June 2005.
Gvax® Myeloma Vaccine. One such vaccine combines a patient's irradiated myeloma cells with Gvax® Myeloma Vaccine (Cell Genesys). Gvax consists of cells that secrete a cytokine known as granulocyte-macrophage colony-stimulating factor (GM-CSF), which stimulates immune responses to vaccines. A Phase I/II trial was conducted to see whether Gvax, administered before and after autologous stem cell transplantation, can stimulate an immune response against the myeloma cells and enhance the response induced by high-dose chemotherapy and stem cell transplantation.
Preliminary results from this study were reported at the American Society of Hematology (ASH) meeting in 2004. (Borrello et al. Blood. 2004;104(11). Abstract 440.) At that time, myeloma cells had been harvested from 22 patients; 18 patients had received the pre-transplant vaccination and 16 had received eight post-transplant vaccinations administered at 3-week intervals starting at 6 weeks post-transplant. Of the 16 patients who had received a transplant, there were 6 complete and 5 partial remissions, for an overall response rate of 69%. Three patients with rising M protein levels early post-transplant had decreased M protein levels following the initiation of post-transplant vaccination, suggesting a possible vaccine-medicated effect. No severe (Grade 3 or Grade 4) vaccine-related toxicities have been observed. Local vaccine injection site reactions were seen in all patients but delayed reactions were infrequent (4 of 10 at 1-year post-transplant).
Despite these encouraging results, Cell Genesys discontinued the Gvax myeloma program in June 2005.
DNA Vaccines
DNA vaccines are composed of fragments of DNA (genetic material, see figure below) that encode specific myeloma proteins or markers and substances to help further activate the immune system.
DNA in the patient's myeloma cells carries a code for specific myeloma antigens which can be targets for immune attack. Graphic courtesy of Freda K. Stevenson
Upon injection into the muscle or skin the DNA code is "read" and the protein is made by the patient's cells. The result is that the protein is then presented to the immune system in a more natural and effective way.
One type of DNA vaccine being developed at the Molecular Immunology Group, Tenovus Laboratory, in Southampton UK utilizes the specific idiotype of a patient's myeloma. To enhance the ability of the patient's immune system to respond to the idiotype, a sequence from a bacterial product has been added (see figure below). The bacterial product selected is derived from the safe vaccine already used against tetanus toxin. The result of this fusion is to dramatically enhance the immune response against the idiotype.
One type of DNA vaccine being developed at the Molecular Immunology Group, Tenovus Laboratory, in Southampton UK utilizes the specific idiotype of a patient's myeloma. To enhance the ability of the patient's immune system to respond to the idiotype, a sequence from a bacterial product has been added (see figure below). The bacterial product selected is derived from the safe vaccine already used against tetanus toxin. The result of this fusion is to dramatically enhance the immune response against the idiotype.
Creation of a DNA vaccine
Graphic courtesy of Freda K. Stevenson
In pre-clinical models, this vaccine induces idiotype-specific T cell responses that suppress myeloma. It is just beginning to be tested in patients following an autologous stem cell transplant. Early results suggest that a substantial and durable immune response is induced and responding T cells were detected in the first patient's blood. A pilot clinical trial is in progress (see list below). In addition, this DNA vaccine is starting to be investigated for use in vaccinating donors who will be providing stem cells for an allogeneic stem cell transplant in order to transfer immunity to the patient. This strategy helps overcome the fact that patients often don't mount a strong immune response against their tumor.
In addition to idiotype, other tumor-associated molecules are being investigated as potential targets for immune attack induced by DNA vaccination. Some of these are cancer-testis antigens, which are present only on cells of the testis (the male reproductive gland) and various types of cancer cells.
In addition to idiotype, other tumor-associated molecules are being investigated as potential targets for immune attack induced by DNA vaccination. Some of these are cancer-testis antigens, which are present only on cells of the testis (the male reproductive gland) and various types of cancer cells.
Viral vector Vaccines
Viral vector vaccines use a virus to transfer specific genes into a patient's cells. The viral genes stimulate the production of a variety of growth factors that enhance the immune response against the tumor cell. Delivery via bacterial vectors can also help to activate immunity, especially in the gut or lung. A further possibility is to combine the various gene-based vaccines by first injecting a DNA vaccine, and then following this with a viral vector delivery of the same tumor-associated antigen. Genomics is offering a myriad of possibilities for targeting cancer cells and vaccine development can take advantage of this.
Ongoing Myeloma Vaccine Trials as of August 2005
Phase I/II
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Cytokines
Cytokines, soluble factors produced by cells, have a wide variety of effects on the immune system and on myeloma cells. Examples of cytokines that are being evaluated in combination with other therapies include
interferon, interleukin 2 (IL-2), and interleukin 12 (IL-12), which help activate tumor-fighting immune cells known as T cells. The cytokine GM-CSF is also being evaluated as part of various combination therapies and vaccine strategies. For example, idiotype is being administered in combination with IL-12 or with IL-12 and GM-CSF in patients with early stage myeloma over a period of 110 weeks. (Hansson et al. Blood. 2004;104. Abstract 1500.)
Ongoing Cytokine Trials as of August 2005
Phase II
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Monoclonal Antibodies
Monoclonal antibodies are modified antibodies that target specific substances and are used as passive immunotherapy to treat various diseases, including certain types of cancer. For example, the monoclonal antibody rituximab (Rituxan®) is used in the treatment of certain B-cell lymphomas, while trastuzumab (Herceptin®) is used in the treatment of certain types of breast cancer. Monoclonal antibodies are sometimes coupled to radioactive particles. In this case, the antibody enhances the delivery of the radioactivity directly to the tumor site. Several monoclonal antibodies directed against markers expressed on myeloma cells are being investigated as potential treatments for myeloma.
Campath® (anti-CD52 antibody, alemtuzumab). Campath (Berlex), a monoclonal antibody approved for use in certain patients with B-cell chronic lymphocytic leukemia, is being investigated in a Phase II trial in relapsed and refractory myeloma. The antibody is directed against the CD52 marker expressed on various normal and cancerous cells.
MRA (humanized anti-IL-6 antibody, atlizumab). One monoclonal antibody being evaluated in Phase I and II trials in myeloma is known as MRA (Chugai Pharmaceuticals). MRA is an antibody that is directed against the human interleukin 6 (IL-6) receptor. IL-6 is a major growth factor for myeloma cells, so the blockade of this receptor may prove effective in limiting myeloma cell growth.
TRM-1 (TRAIL-R1 monoclonal antibody). TRM-1 (Human Genome Sciences) is directed against a specific receptor on myeloma cells known as TRAIL (TNF-related apoptosis-inducing ligand). Binding of the antibody to TRAIL contributes to myeloma cell death. TRM-1 is being evaluated in a Phase I trial in myeloma.
AHM (anti-HM1.24 monoclonal antibody). Another monoclonal antibody in Phase I clinical trials is AHM (Chugai). HM1.24 is a marker expressed on myeloma cells. Antibodies to HM1.24 have been shown to induce killing of myeloma cells in the lab and in animal models.
SGN-40 (anti-huCD40 mAb). SGN-40 (Seattle Genetics) is a monoclonal antibody directed against a receptor on myeloma cells known as CD40. It is being investigated in a Phase I trial in refractory and relapsed myeloma. Preliminary evidence for antitumor activity in this ongoing dose-ranging study is encouraging. (Hussein et al. ASCO 2005. Abstract #6581.)
mKap. mkap is a monoclonal antibody that is specific for free human kappa light chains (the small arms of antibody molecules) and a marker on the surface of plasma cells. This antibody induces apoptosis of myeloma cell lines in the laboratory and exhibited antitumor activity in a mouse model of disease. (Asvadi et al. Blood. 2004;104. Abstract 2416.)
Campath® (anti-CD52 antibody, alemtuzumab). Campath (Berlex), a monoclonal antibody approved for use in certain patients with B-cell chronic lymphocytic leukemia, is being investigated in a Phase II trial in relapsed and refractory myeloma. The antibody is directed against the CD52 marker expressed on various normal and cancerous cells.
MRA (humanized anti-IL-6 antibody, atlizumab). One monoclonal antibody being evaluated in Phase I and II trials in myeloma is known as MRA (Chugai Pharmaceuticals). MRA is an antibody that is directed against the human interleukin 6 (IL-6) receptor. IL-6 is a major growth factor for myeloma cells, so the blockade of this receptor may prove effective in limiting myeloma cell growth.
TRM-1 (TRAIL-R1 monoclonal antibody). TRM-1 (Human Genome Sciences) is directed against a specific receptor on myeloma cells known as TRAIL (TNF-related apoptosis-inducing ligand). Binding of the antibody to TRAIL contributes to myeloma cell death. TRM-1 is being evaluated in a Phase I trial in myeloma.
AHM (anti-HM1.24 monoclonal antibody). Another monoclonal antibody in Phase I clinical trials is AHM (Chugai). HM1.24 is a marker expressed on myeloma cells. Antibodies to HM1.24 have been shown to induce killing of myeloma cells in the lab and in animal models.
SGN-40 (anti-huCD40 mAb). SGN-40 (Seattle Genetics) is a monoclonal antibody directed against a receptor on myeloma cells known as CD40. It is being investigated in a Phase I trial in refractory and relapsed myeloma. Preliminary evidence for antitumor activity in this ongoing dose-ranging study is encouraging. (Hussein et al. ASCO 2005. Abstract #6581.)
mKap. mkap is a monoclonal antibody that is specific for free human kappa light chains (the small arms of antibody molecules) and a marker on the surface of plasma cells. This antibody induces apoptosis of myeloma cell lines in the laboratory and exhibited antitumor activity in a mouse model of disease. (Asvadi et al. Blood. 2004;104. Abstract 2416.)
Ongoing Monoclonal Antibody Trials as of August 2005
Phase II
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Manipulation of Immune Cells
Another example of immunotherapy is the manipulation of immune cells to help improve outcome and reduce the rate of relapse. A number of diverse strategies involving immune cells are being investigated in myeloma.Donor lymphocyte infusion (DLI). One experimental technique that harnesses the beneficial effects of immune cells is known as donor lymphocyte infusion (DLI). This technique is used following high-dose chemotherapy and allogeneic stem cell transplant, a type of transplant whereby a patient receives stem cells from a matched donor. During the process of allogeneic stem cell transplantation, donor immune cells present in the transplant help attack the patient's myeloma cells, a phenomenon known as graft-versus-myeloma effect. With a donor lymphocyte infusion, the patient receives additional immune cells from that same donor some time after the stem cell transplant. It is thought that this additional infusion of immune cells can help continue to control the disease.
There have been several reports of complete responses achieved with donor lymphocyte infusions following allogeneic stem cell transplantation. (Lokhorst et al, 1997; Salama et al, 2000). However, response is often associated with significant graft-versus-host disease.
Donor lymphocyte infusions are also being utilized following non-myeloablative (mini-allogeneic) stem cell transplantation. The reduced-intensity chemotherapy is thought to result in reduced toxicity.
Active immunization of stem cell transplant donors. Another technique under investigation in a National Institutes of Health clinical research study is active immunization of the donor who will be providing stem cells for a certain type of allogeneic stem cell transplant. The donor in this case is the patient's tissue-matched sibling, who will be immunized with the patient's purified myeloma protein along with GM-CSF. It is hoped that the donor will develop tumor-specific immunity. The patient, who is immunized as well, will then receive a non-myeloablative (mini-allogeneic) transplant, which contains stem cells from the immunized donor. The goal of this process is to transfer tumor-specific immunity that is induced in the stem cell donor to the patient to help reduce relapse. Preliminary results reported at ASH in 2004 confirm that such vaccines can be safely and effectively given to normal stem cell donors and suggest that tumor-specific immunity can be induced and passively transferred. (Bishop et al. Blood. 2004;104. Abstract #814.)
The initiation of this trial was prompted by encouraging results of an earlier similarly designed study conducted in five patients who received allogeneic transplants from a sibling following immunization with myeloma protein. (Neelapu et al. Blood. 2004;104. Abstract 3340.) These data suggest that such vaccination induces specific immunity in the donor that can be transferred to the patient and is associated with prolonged disease-free survival. Two patients remain in complete remission 8 years and 7 years after transplant.
A study aiming to induce anti-myeloma immune responses in the donors of allograft siblings is also recruiting in Southampton, UK. The patients' myeloma cells are used to identify the unique immunoglobulin genes from the tumor and to then produce a patient specific vaccine. Before the harvest of the allograft from the sibling donor, the donor receives the DNA vaccine by intramuscular injection.
Marrow infiltrating lymphocytes (MILS). One means of attacking myeloma is to generate an immune response outside the body and infuse it back into the patient. One experimental technique being investigated at Johns Hopkins involves harvesting immune cells from a patient's bone marrow. These immune cells, known as marrow infiltrating lymphocytes (MILS), appear to be more effective at killing myeloma cells than immune cells circulating in the blood. MILS are stimulated and grown in the lab and then returned to the patient. Because it involves the transfer of cells, this type of passive immunotherapy is also referred to as adoptive immunotherapy.
Ongoing Immune Cell Trials as of August 2005
Phase II
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New Research and Targets for Immunotherapy
Before more effective immunotherapy strategies can be developed, a better understanding of the immune defects that prevent myeloma patients from mounting a strong response against their tumor cells is required. Researchers are beginning to identify these defects, which include functional deficiencies in T cells and dendritic cells, excessive production of inhibitory cytokines, and inadequate production of stimulatory cytokines.
Genetic studies have identified two cancer-testis antigens that are present in myeloma cells with abnormal cytogenetics and in cells from patients with relapsed disease (NY-ESO-1 and MAGE-A3) as potential targets for immunotherapy. (Gupta et al. Hematol J. 2003;4(suppl 1):S267. Abstract 402.)
A number of other novel immune strategies are also being investigated in preclinical studies. One of these is a technique referred to as virus therapy or virotherapy. Measles virotherapy utilizes a specific type of engineered measles virus to infect and kill myeloma cells. (Russell et al. Blood. 2003;102(11). Abstract 249.)
Genetic studies have identified two cancer-testis antigens that are present in myeloma cells with abnormal cytogenetics and in cells from patients with relapsed disease (NY-ESO-1 and MAGE-A3) as potential targets for immunotherapy. (Gupta et al. Hematol J. 2003;4(suppl 1):S267. Abstract 402.)
A number of other novel immune strategies are also being investigated in preclinical studies. One of these is a technique referred to as virus therapy or virotherapy. Measles virotherapy utilizes a specific type of engineered measles virus to infect and kill myeloma cells. (Russell et al. Blood. 2003;102(11). Abstract 249.)
Other Ongoing Immunotherapy Trials as of August 2005
The following is an observational study being conducted to measure patients' immune response to their own tumor:
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Reviewed by:
Freda K. Stevenson, DPhil
Professor, University of Southampton
Molecular Immunology Group
Tenovus Laboratory
Southampton University Hospitals Trust
Southampton, UK