Immune Responses by Dendritic Cell Vaccination

Anti-Tumor Immune Response: The Foundation

Even when a tumor is successfully removed, a few cells are almost invariably left behind. These often are treated with radiation or chemotherapy to keep them from growing, but certain types of aggressive, malignant cells are especially difficult to contain.

Among the most persistent are glioblastoma multiforme tumor cells. This cancer is among the most common types of brain tumors. They tend to grow quickly, invade surrounding tissue, and recur frequently. Survival rates have historically been extremely low.

Dendritic cell immunotherapy - developed at the Institute to fight these malignant brain tumors - creates a vaccine from the cells of a tumor that has been surgically removed.

In the laboratory, cancer proteins extracted from the tumor are combined and cultured with dendritic cells taken from the patient's blood. Dendritic cells, also known as antigen-presenting cells, identify tumor cells for the immune system's cancer-fighting T-cells. The new dendritic cells resulting from this union are re-injected into the patient, where they recognize and destroy any lingering malignant tumor cells. Several injections of a small amount of the vaccine are typically scheduled over a six-week period.


Current Developments and Research Progress

Although significant advances have been made using radiation, surgery and chemotherapeutics to increase the survival of patients with glioblastoma multiforme (GBM), these advances have been modest with only 2-3 month increases in survival. In contrast, the Institute has confirmed the ability to mount significant biological activity through dendritic cell vaccination approaches and provide a rationale to address the infiltrating pockets of tumor cells. One compelling aspect of the Cedars-Sinai studies has been both clinical and mechanistic evidence for the ability of immunotherapy to sensitize glioblastomas to chemotherapy(6). Not only does the immunotherapy itself induce cytotoxicity (quality of being toxic to cells), but it makes tumors more amenable to drug therapy. The Institute recently demonstrated that temozolomide improves the immunogenicity (ability to provoke an immune response) of glioblastomas and cancels the immunosuppression seen both locally and systemically.

Scientists at the Neurosurgical Institute have shown that dendritic cell immunotherapy (DCIT) induces a cytotoxic T cell response to autologous tumor and specific-tumor associated antigens in a subset of patients with glioblastoma (1,4,6,7). The dendritic cell vaccination also induces cytotoxic memory T cells to localize in intracranial tumor in a subset of patients (1,4,6,7). In these studies, vaccinated glioblastoma patients have prolonged survival compared to RTOG recursive partitions and cohorts controlled for age, Karnofsky performance scores, and degree of resection (1,4,6,7). In the past, the survival of glioblastoma patients within each of the Institute's Phase I and II trials was highly correlated with whether a cytotoxic T cell response was observed after dendritic cell vaccination.

When de novo (newly treated) glioblastoma patients from our Phase I and Phase II trials were retrospectively partitioned into 1) those patients that received chemotherapy after dendritic cell vaccination; 2) those that did not receive chemotherapy and 3) those patients that received chemotherapy alone -- patients who received chemotherapy following immunotherapy demonstrated longer progression free survival and overall survival compared to the other two groups.

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Recent Publications
  1. Wheeler CJ, Black KL, Liu G, Mazer M, Zhang X, Pepkowitz S, Goldfinger D, Ng H, Irvin D, Yu JS. Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients. Cancer Res 68(14):5955-64, 2008.
  2. Akasaki C, Liu G, Chung NH, Ehtesham M, Black KL, Yu JS. Induction of a CD4+ T regulatory type-1 response by cyclooxygenase-2 overexpressing glioma. J Immunology 173(7):4352-9, 2004.
  3. Liu G, Yu JS, Zeng G, Yin D, Xie D, Black KL, Ying H. AIM-2: A Novel Tumor Antigen Is Expressed and Presented by Human Glioma Cells. J Immunotherapy 27:220-6, 2004.
  4. Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen specific cytotoxic T cells in patients with malignant glioma. Cancer Res 64:4973-9, 2004.
  5.  Liu G, Ying H, Zeng G, Wheeler CJ, Black KL, Yu JS. HER-2, gp100, and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells. Cancer Res 64:4980-4986, 2004.
  6. Wheeler CJ, Das A, Liu G, Yu JS, Black KB. Clinical responsiveness of glioblastoma to chemotherapy after vaccination. Clin Cancer Res 10(16):5316-26, 2004.
  7. Yu JS, Wheeler CJ, Zeltzer PM, Finger D, Lee PK, Pins R, Yong WH, Thompson RC, Riedinger M, Zhang W, Black KL. Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res 61:842-847, 2001. (selected as cover illustration)
     

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