The Blocking vs Depletion Model of Immune Checkpoint Inhibitor Therapy for Cancer

Abstract

Immune Checkpoint Inhibitor (ICI) therapy is the most exciting development in cancer treatments in recent years. As of the end of 2021, more than a hundred of clinical trials have been carried out by several major drug makers and research hospitals all over the world just to explore the use of ICI antibodies in almost every type of cancer and under various clinical settings. These clinical trials have resulted waves of good news in every year’s major academic conferences and FDA approvals, and now ICI therapy is in the move to take over traditional therapy to become the major player in clinical management of cancer. On the other hand, most of these clinical trials have failed to show clear benefits in most cancer patients, and only few have been reported in public. In real-world clinical setting, ICI antibodies are being massively and sometimes abusively prescribed for almost every desperate situation with clear clinical benefit in only a few (<10%). Yet, the enthusiasm behind ICI therapy is not dampened by the massive clinical failure but has been growing. The reason for the consistent enthusiasm among clinicians and patients is the miracle-like clinical responses seen in some of the responders that even including late-stage hopeless cases. Every clinician wants to repeat this miracle in the next seemingly identical patient, and every patient and their family members want to believe that they are in line for that miracle. But the reality is disheartening in that clinicians do not see the predictable repeat of miracle-like responses in seemingly identical patients and most patients selecting ICI therapy as the last straw in life did not benefit from it, if not hurt by it. What then are the reasons that ICI therapy is so impressive when working and so unpredictable in responses? This review attempts to draw some mechanistic aspects based on our own experiences in ICI therapy and to come up with a different explanation for the unexplained clinical observations. The goal of this review is to alert the clinical field about the danger and irreversible damages that wrongly used ICI antibodies may cause, and at the same time to introduce some preliminary criteria to select proper patient for the benefits and to avoid the harms of ICI therapy.