Treatment of a Patient by Vaccination
Treatment of a Patient by Vaccination
Dendritic cells (DCs) are antigen-presenting cells that play a central role in the initiation and modulation of antitumor immune responses. In this pilot study, we investigated the ability of autologous DCs pulsed ex vivo with allogeneic major histocompatibility complex class I-matched glioblastoma peptides to stimulate host antitumor immune responses when injected as a vaccine.
A patient with recurrent brainstem glioblastoma multiforme (GBM) received a series of three intradermal immunizations of antigen-pulsed DCs on an outpatient basis following surgical debulking of her posterior fossa tumor. Dendritic cell vaccination was well tolerated, and no clinical signs of autoimmunity or experimental allergic encephalomyelitis were detected. She developed a measurable cellular immune response against the allogeneic glioblastoma peptides used in her vaccine preparation, as demonstrated by in vitro T-cell proliferation assays. In addition, increased T-cell infiltration was noted within the intracranial tumor site in the biopsy sample obtained following DC vaccination. An objective clinical response, however, was not evident, and this patient eventually died 21 months after her disease was diagnosed.
To our knowledge, this is the first patient with brain cancer ever to be treated with DC-based immunotherapy. This case illustrates that vaccination with DCs pulsed with acideluted glioblastoma peptides is feasible and can induce systemic antigen-specific immunity in a patient with recurrent GBM. Additional studies are necessary to determine the optimum DC doses and antigen loading conditions that may translate into clinical effectiveness and survival benefit for patients with brain tumors. Phase I trials for malignant glioma are currently underway.
As surgery, chemotherapy, and radiotherapy have failed to improve the poor prognosis of patients with GBM, there has been increased motivation to develop novel, alternative therapies for these deadly neoplasms. One such alternative is to utilize the immune system to specifically target and eliminate tumor cells on the basis of antigen expression and recognition. It is now well established that tumor cells express certain proteins that are different from nontumor cells and, additionally, that the immune system has cells, particularly cytotoxic T lymphocytes, that can recognize tumor antigens and kill tumors. However, a major problem is that antitumor immunity is not effectively induced in tumor-bearing hosts. Although tumors have antigens for T cells, these do not appear to be immunogenic in vivo. One possible reason is that there is insufficient tumor antigen presentation to elicit T-cell immunity. This is particularly true for brain tumors, as T cells are not readily evident within the immune-privileged CNS unless T-cell immunity is generated.
Dendritic cells are antigen-presenting cells specialized for the induction of primary T-cell responses. They possess the necessary costimulatory molecules and cytokine profiles for eliciting effective T-cell immunity. These cells capture and convert protein antigens into peptide fragments, load them onto MHC molecules on their cell surfaces, and then present the peptide-MHC complexes to T lymphocytes for stimulating antigen-specific T-cell immune responses. Dendritic cells play a central role in the initiation of antitumor immune responses and are considered to be promising adjuvants for inducing immune responses to cancer. Initial data obtained from clinical trials of DC-based vaccines for B-cell lymphoma, melanoma, prostate cancer, and renal cell carcinoma have recently been published, and the results appear to be encouraging. In different animal models, the capacity of DCs to elicit antitumor immune responses for the treatment of CNS tumors has been demonstrated by our laboratory and others. As a feasibility study and preliminary proof of the concept for clinical trials in patients with brain tumors, we report on the results of the first patient with GBM to be treated with a full course of peptide-pulsed DC immunotherapy. This single-patient trial was conducted at UCLA Medical Center in April of 1997 and, to our knowledge, represents the first human test of DC immunotherapy for brain cancer.
Dendritic cells (DCs) are antigen-presenting cells that play a central role in the initiation and modulation of antitumor immune responses. In this pilot study, we investigated the ability of autologous DCs pulsed ex vivo with allogeneic major histocompatibility complex class I-matched glioblastoma peptides to stimulate host antitumor immune responses when injected as a vaccine.
A patient with recurrent brainstem glioblastoma multiforme (GBM) received a series of three intradermal immunizations of antigen-pulsed DCs on an outpatient basis following surgical debulking of her posterior fossa tumor. Dendritic cell vaccination was well tolerated, and no clinical signs of autoimmunity or experimental allergic encephalomyelitis were detected. She developed a measurable cellular immune response against the allogeneic glioblastoma peptides used in her vaccine preparation, as demonstrated by in vitro T-cell proliferation assays. In addition, increased T-cell infiltration was noted within the intracranial tumor site in the biopsy sample obtained following DC vaccination. An objective clinical response, however, was not evident, and this patient eventually died 21 months after her disease was diagnosed.
To our knowledge, this is the first patient with brain cancer ever to be treated with DC-based immunotherapy. This case illustrates that vaccination with DCs pulsed with acideluted glioblastoma peptides is feasible and can induce systemic antigen-specific immunity in a patient with recurrent GBM. Additional studies are necessary to determine the optimum DC doses and antigen loading conditions that may translate into clinical effectiveness and survival benefit for patients with brain tumors. Phase I trials for malignant glioma are currently underway.
As surgery, chemotherapy, and radiotherapy have failed to improve the poor prognosis of patients with GBM, there has been increased motivation to develop novel, alternative therapies for these deadly neoplasms. One such alternative is to utilize the immune system to specifically target and eliminate tumor cells on the basis of antigen expression and recognition. It is now well established that tumor cells express certain proteins that are different from nontumor cells and, additionally, that the immune system has cells, particularly cytotoxic T lymphocytes, that can recognize tumor antigens and kill tumors. However, a major problem is that antitumor immunity is not effectively induced in tumor-bearing hosts. Although tumors have antigens for T cells, these do not appear to be immunogenic in vivo. One possible reason is that there is insufficient tumor antigen presentation to elicit T-cell immunity. This is particularly true for brain tumors, as T cells are not readily evident within the immune-privileged CNS unless T-cell immunity is generated.
Dendritic cells are antigen-presenting cells specialized for the induction of primary T-cell responses. They possess the necessary costimulatory molecules and cytokine profiles for eliciting effective T-cell immunity. These cells capture and convert protein antigens into peptide fragments, load them onto MHC molecules on their cell surfaces, and then present the peptide-MHC complexes to T lymphocytes for stimulating antigen-specific T-cell immune responses. Dendritic cells play a central role in the initiation of antitumor immune responses and are considered to be promising adjuvants for inducing immune responses to cancer. Initial data obtained from clinical trials of DC-based vaccines for B-cell lymphoma, melanoma, prostate cancer, and renal cell carcinoma have recently been published, and the results appear to be encouraging. In different animal models, the capacity of DCs to elicit antitumor immune responses for the treatment of CNS tumors has been demonstrated by our laboratory and others. As a feasibility study and preliminary proof of the concept for clinical trials in patients with brain tumors, we report on the results of the first patient with GBM to be treated with a full course of peptide-pulsed DC immunotherapy. This single-patient trial was conducted at UCLA Medical Center in April of 1997 and, to our knowledge, represents the first human test of DC immunotherapy for brain cancer.
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