Challenges Facing Cancer Vaccines

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S. Jack Wei, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: July 2, 2004

Why has it been so difficult to make a cancer vaccine that works?²

The problem with cross-reactivity

Cancer vaccines need to be directed at antigens that are expressed by the tumor but not by the normal cells. If the antigen that is used is also expressed in normal cells, the immune response generated by the vaccine can attack normal tissue as well. This cross-reactivity can increase the toxicity of the treatment, interfering with one of the biggest potential advantages of cancer vaccines: the ability to specifically target the cancer cells without damaging the normal cells.

Cancer cells inhibit co-stimulation of the immune response

Co-stimulation of the immune response must occur for there to be a vigorous immune response. Tumor cells secrete chemical factors that interfere with co-stimulation of the immune response. Even if an APC is able to present antigens to T-cells, the immune response is often limited without co-stimulatory signals. Cancer vaccines that present the TAA to the immune system without increasing co-stimulation run into the same problem. The immune response is often too weak for any significant effect on the tumor to occur. In order to solve this problem, cancer vaccines are often designed to provide co-stimulation in addition to the TAA in order to increase the immune response.

The larger the tumor, the more difficult it is to destroy all of the cancer cells

When individual cancer cells are found, the immune system can easily clear them from the body. Unfortunately, by the time most cancer vaccines are given, the tumors are large and much more difficult to treat. In addition to the sheer number of cells that need to be destroyed, as tumors grow, there are areas within the tumor that become difficult for the immune system to reach. These areas become protected from the effect of the cancer vaccine.

The immune system slows down as we age

The thymus is an organ in the chest that functions to produce T-cells (the T stands for thymus). It functions in childhood and slows down with time, eventually becoming inactive in adults. This is one of the reasons that vaccines are often given in infancy and childhood. The immune response of adults is dependent on the population of T-cells that was produced during childhood. Over time, this response becomes less vigorous. Cancer vaccines face the challenge of inducing immune responses in a population of patients whose immune systems are naturally slowing down.

Cancer cells themselves are immunosuppressive

Cancer cells can suppress the immune system in a number of ways. They can block co-stimulation, preventing a vigorous immune response. Cancer cells can inhibit the maturation or function of APCs, blocking the presentation of TAAs to lymphocytes. In addition, cancer cells can directly block the activation of lymphocytes, preventing a response after the antigens have been presented.