The Holy Grail of cancer therapy has been to cause tumors in patients to disappear with minimal adverse effects on normal tissues. It has been clear, in concept, that one way to achieve this end would be to use the specificity implicit in the human immune system to recognize and destroy cancer cells while sparing normal cells.
Over the last 40 years there have been many attempts to stimulate the immune system in cancer patients in the hope that the this nonspecific stimulation would cause the immune system to recognize and destroy cancer cells. The literature is peppered with trials using non-specific immune stimulating adjuvants like BCG (Bacillus Calmette Guerin). Although some studies suggested some traces of antitumor activity, the overall assessment was negative. Dramatic and clinically meaningful responses didn’t occur. Other approaches to stimulate immunity by infusing patients with cells thought to have antitumor activity using auto and allogeneic stem cell transfer were both toxic and clinically disappointing. The adoptive transfer lymphoid cells, which had been ‘educated’ in vitro to recognize and destroy patient’s cancers (IL2/LAK and TIL infusions) tended to be very toxic. Although significant responses occurred, they were rare and were obtained with toxic side effects that were frequently very severe.
Recently, there have been examples of more significant, more specific and more sophisticated immune manipulation that may be the leading edge of immune therapies that will be widely applicable to patients with cancer. What may be a ‘breakthrough strategy’ of immune manipulation in cancer has been demonstrated in melanoma. The FDA recently approved the monoclonal antibody Ipilimumab for use in patients with metastatic melanoma. This therapy is unique because its mechanism of action is to increase T-cell antitumor activity by blocking factors suppressing T-cell antitumor activity. Thus the intrinsic antitumor immunity in patients is allowed to function and results in meaningful clinical results (improved survival). Ipilimumab has the capability of producing autoimmunity since it blocks suppression of immune activity. However, clinical toxicity seems manageable. Other types of cancer may benefit from Ipilimumab or therapies with a similar mechanism of action.
The second example of a very intriguing immune manipulation in cancer has been reported this week from Rosenberg and colleagues work at the NCI. This group has been studying Adoptive Cell Transfer (ACT) in patients with metastatic cancer for the last 35 years. ACT, although frequently very toxic especially when given with high dose interleukin-2 (IL2), occasionally resulted in tumor regression. Rosenberg’s group now report results in a patient with metastatic bile duct carcinoma who had had very meaningful tumor responses to ACT using a subset of TIL (Tumor Infiltrating Lymphocytes) selected to be cytotoxic to cancer cells carrying a mutation, ERBB2, of an ERBB2 interacting protein. Toxicity of ACT in this setting is manageable and the patient’s performance status after therapy is excellent.
So why be excited about Ipilimumab and the admittedly, very early results of the newest iteration of ACT from the NCI group? First, the use of immunotherapy may be able to circumvent inherent chemotherapy resistance. Secondly one can imagine that ACT with specific tumorcidal T-cells might combine very nicely with Ipilimumab like agents which enhance T-cell mediated tumor cell death. Further evaluation of this strategy may warrant further testing.
Maybe, indeed, we are leaving the age of wishful thinking and are closing in on a new age of tumor shrinkage in the immune therapy of cancer.
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