By David Warmflash
Immunotherapy for cancer is based on the idea that the immune system can be modulated to improve tumor-specific responses and to interfere with tumor tolerance. Immune activity against malignant tissue depends on the activation of innate immune cells, as well as natural killer (NK) cells, macrophages, neutrophils, mastocytes, and dentritic cells (DCs). Found in nearly every kind of body tissue, DCs capture antigens, including those on tumor cells, and carry them to secondary lymphoid organs. There, they activate naïve T cells. Control of the various immune cells depends on agents known as cytokines and chemokines, and on immune cells known as B and T lymphocytes.
Unlike standard cancer therapy, which is based on more of a general attack-all-rapidly-dividing-cells strategy, immunotherapy targets specific cell types based on specific surface antigens.
There are different kinds of immunotherapy. Passive immunotherapy employs monoclonal antibodies that bind antigen epitopes on tumors. The same antibodies can be complexed with tumor-killing drugs or agents that sensitize tumor cells to chemotherapeutic agents, radiation beam therapy, or radioactive isotopes (radionuclides). Another class of passive immunotherapy involves stimulation using the cytokine interleukin (IL)-12. Active immunotherapy uses vaccines developed from DCs. One way to make such a vaccine is to pulse DCs with antigens specific to the patient’s tumor. Alternatively, entire malignant cells can be fused to DCs.
Immunotherapy is approved by the Food and Drug Administration (FDA) for treatment of prostate cancer and malignant cutaneous melanoma. However, by secreting various agents to inhibit cytotoxic immune responses, some cancers can learn to tolerate a patient’s immune system. One example is glioblastoma multiforms (GBM), an aggressive brain tumor. In addition to suppressing immune responses, GBM and other high-grade gliomas are protected from therapy by the blood-brain barrier (BBB), which keeps out all but a few drugs. However, these tumors also cause the BBB to break down to a certain degree. Consequently, the hope is that active immunotherapy will prove to be a viable strategy, and some recent trials show that this approach leads to improved survival compared with patients given standard treatment alone.
Results from phase I and phase II trials suggest that both DC vaccines, and another type of vaccine known as formalin-fixed vaccines, can stimulate the immune system to attack high-grade glioma tissue with only slight toxic effects. In addition to being part of the primary therapy, immunotherapy may be useful in an adjuvant role in the setting of GBM.
Cancer therapy has developed in baby steps, but substantially over the last several decades. With the molecular targeting capabilities of the immune system and its component, gradually we are transitioning from a sledgehammer to precision therapy, and nowhere will this be more beneficial than in the brain.