Q: Surgery and radiation treatment for many cancers are now being followed by not only adjuvant chemotherapy but also a huge panoply of targeted therapies based on precision diagnostics. In your crystal ball, how do you see immunotherapy evolving in relation to targeted therapies based on cancer genomic findings? Exclusive or sequenced or blended?
A: For decades the interplay of the neoplastic process with the immune system has been described. There are several longstanding observations that are relevant:
First, in a variety of animal models of cancer, the adaptive (cellular or humoral) and innate immune systems (natural killer cells, proteins, etc)_can be primed or manipulated to limit or eradicate tumors, or delay their development in high risk settings.
Second, patients who have inherited a defective immune system, undergone stem cell transplants, or had their immune system altered by chemotherapy have a higher than expected rate of primary or secondary neoplasms.
Third, despite apparently normal immune systems and useful cytotoxic therapies, many patients with solid tumors progress. While the therapies themselves may alter the effects of the immune system, cancers seem capable of eventually avoiding immune surveillance either by becoming less immunogenic and/or actively suppressing immunity. It may be that some cancers in early stages are effectively eliminated by our immune systems but those we detect are not.
Historically, surgery is the most effective cancer treatment. Many early stage solid tumors are cured by excision. In some cases, there is a high reoccurrence rate but this is believed to reflect a genetic predisposition or occasionally dissemination as the result of the surgical procedure. Cytotoxic chemotherapy does not usually cure cancer.
Two developments have shown promise in providing oncologists with new and effective treatments for cancers that cannot be cured by simple surgical excision. As we have improved our methods of genomic analysis of primary tumors, metastases or circulating components associated with tumors (cell free DNA or circulating tumor cells), cancer somatic mutations have been noted. Some of these affect metabolic or cellular systems that are “targetable” by small molecule or biologic pharmaceuticals. While the responses to these treatments can be small, some dramatic and effective courses have been reported. These treatments may act directly on tumor metabolism, may make the tumor more readily attacked by our immune systems or both.
A second development has been therapies that directly alter immune responsiveness. The administration of PD1 or PDL1 agents in several differing solid tumor types appears to unblock the immune system and allow it to more efficiently fight tumors. The result has been, despite some significant side effects, profound and long lasting remissions in an unexpectedly large number of patients. The best time to administer these agents and exactly which tumors are most likely to respond remains in need of further clinical investigations.
I believe that in most cases, targeted therapies should be administered early in the course of non-resectable tumors. Their side effect profile and specificity make them an improvement over standard of care cellular poisons. I also believe that once a response appears to be initiated that it should be consolidated by unleashing the patient’s immune system with current agents, vaccines or other immunostimulants. This will lead to the highest rate of cure in my opinion.
Of course, tumors will escape therapies by mutating further making their metabolism more resistant to targeted treatments and changing their “antigenic load” to avoid developing immunity or by directly suppressing the immune system. Thus, monitoring and changing both the targeted treatments and immunomodulation will eventually be necessary in effective chronic cancer care.
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