Williams Cancer Institute



Hyperprogression is an actual increase in the cancer growth rate caused from the treatment with immune checkpoint inhibitors (PD-1/PD-L1) such as Opdivo and Keytruda. Reports indicate this may occur in 4-29% of patients treated in multiple cancer types. It is not as clearly defined and can be confused with pseudoprogression, where patients have an initial increase in tumor size first and ultimately a decrease. The degree of tumor increase with hyperprogression is greater than that seen with pseudoprogression, with often a doubling in tumor size and the development of new tumor locations as compared to the pre-treatment and first post-treatment scans. It is important to note that hyperprogression will shorten the patient’s lifespan, meaning it will make them worse than if they were not treated at all. Frankly, that is a little scary.
Studies have indicated an association with MDM2 gene amplification and EGFR aberrations. However, these are still not clear. More promising, in a recent study published in Clinical Cancer Research by Lo Russo, et al., Sept 11, 2018, they implicated tumor-associated macrophages (TAMs) as potentially being a major culprit. Basically they describe that part of the PD-1/PD-L1 antibody (drugs such as Opdivo/ Keytruda to block these receptors) binds to a part of the tumor- associated macrophages (TAMs) and may actually activate them to become more tumor-protecting. When this part of the antibody (drug) was removed, the enhanced growth rate of cancer was not seen. In the mouse model they also found that using clodronate, a first generation bisphosphonate used for the treatment of osteoporosis (approved in many countries, but not the U.S.), was able to reduce the macrophages and hyperprogression.

As I have mentioned, tumor-associated macrophages may be an important area of immunotherapy resistance. This will be an area that needs to be addressed with combination therapy. Several drugs are in development for this, with one of the most promising being CSF-1R inhibitors. Also, an Anti-MARCO antibody was able to convert the tumor-protecting macrophages into the tumor-attacking type.

As you learned earlier in Chapter 13, 6-Gingerol is a natural substance that can inhibit TAMs, though probably not to the level of these experimental drugs, but at least it is easily available. Clodronate may be an option as well, at least in countries where it is approved. Studies have shown that zoledronic acid (Zometa) has similar effects and is approved in the U.S. The extract from milk thistle, Silibin may also have a role in inhibiting cancer protecting tumor-associatedmacrophages (TAMs). Also don’t forget mangostin, a human STING agonist mentioned earlier, because it not only activates STING, but also converts TAMs from the M2 to M1 type (tumor-protecting to tumor-attacking). However, keep in mind that this would need to be injected into a tumor directly. In summary, even though the goal of immunotherapy is to have a successful cancer treatment with less side effects of traditional chemotherapy and radiation, there remain many potential serious side effects that can be caused byimmunotherapies, as well. These must be monitored and in certain cases may require treatment. It is important for the patient to be aware of these potential issues and notify their doctor immediately if concerning symptoms develop.

Reference: Jason R. Williams, 15 Oct 2019, The Immunotherapy Revolution: The Best New Hope For Saving Cancer Patients’ Lives, https://williamscancerinstitute.com/the-immunotherapy-revolution

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