In the story of Goldilocks and the three bears, a little girl tastes three different bowls of porridge made by a family of bears. She discovers that one is too hot, the second too cold, and the third just the right temperature. This philosophy of balance has since proven to be a great window to gauge the right measure across a wide range of disciplines.
The field of medicine uses this concept of ‘just the right amount’ and holds the key to awakening the body’s immune responses to cancer therapies. Despite emerging clinical trial data and an optimistic stream of drug approvals, efforts to rationally stratify patients to treatment regimes that achieve equipoise with respect to drug combinations and therapy intensity with optimal clinical outcomes is still underway.
Patient stratification based on mutations and biomarkers is favored for best outcomes. Genomic alterations that are correlative to treatment outcomes are favored as first-line monotherapy. If the mutations or genomic signatures are from divergent networks, a combination regime is preferred. Such combinations could be either targeted therapies with chemotherapy or immune therapies with chemotherapy
However, it’s noteworthy that cytotoxicity alone is insufficient for suppressing tumor growth, especially due to the accumulating chemoresistance. Rather, it is the synergistic effect of cytotoxicity as well as the breaking of immune tolerance and consequent recruitment of cytotoxic T lymphocytes that keeps tumor populations in check.
Whether sequential use of these agents and/or in combination might further amplify benefit in specific subgroups and with manageable toxicities remains to be seen, and is the subject of numerous ongoing trials. Several studies indicate that optimal chemotherapy requires the identification of a ‘Goldilocks Window’ in which treatment can both induce cytotoxic effects in the tumor and enhance the immune response to it. Therefore, instead of the one-size-fits-all paradigm of fixed therapy regimens, the patient’s immune biology should be a key consideration when developing personalized chemotherapy strategies.
Memory cell population sizes are variable among patients. Patient memory cell numbers significantly influence the optimum chemotherapy dose. Generally, there is a minimum memory-cell population size that is necessary for any given strength of chemotherapy to be successful. Above this threshold, the more memory cells there are, the better the improvement with stronger doses of therapy. Furthermore, if memory cells are below the minimum threshold, the optimal strategy is to use strong chemotherapy, since the immune system will not contribute to tumor regression.
Many studies have consistently shown that there is an inherent disadvantage to high-dose chemotherapy. There is a gradual decrease in the cytotoxic T lymphocytes population over multiple rounds of treatment due to the net loss that stronger dosing causes in memory T cell populations. It is these memory cells that are affected the most by chemotherapy, since they can only recover relatively slowly. In short, there is a trade-off between having chemotherapy strong enough to sufficiently break tolerance, but mild enough to leave sufficient memory T cells for adequate cytotoxic T lymphocyte expansion.
Akin to the story of Goldilocks and the three bears, the ultimate goal is the balancing of these two immunological goals, leading to an intermediary chemotherapy strength that is ‘just right’.