Cancer therapy sees a stunning success, while Alzheimer Disease (AD) therapy seems stuck in the mud. Why is there such a contrast?
The Am Soc Clin Oncology had a special session in June to discuss an amazing result: All 14 patients with locally advanced rectal cancer had 100% complete radiographic responses, and the therapy did not include any conventional chemo, radiation or surgery!! Results were presented as an abstract. Meanwhile, in Alzheimer therapy, there are more reported failures (crenezumab anti-amyloid; semorinemab anti-tau).
How is any of this cancer news relevant to AD / dementia clinical therapy research? Well, will we ever see a substantial dementia therapy in our lifetimes? Can anything from the development of cancer therapeutics transfer over to dementia? Let’s explore the rectal cancer story a bit more:
The medical data [with a checkpoint inhibitor agent called dostarlimab] was published in NEJM (Jun 23 issue). These cases were very highly selected, and all had a specific mismatch repair genetic defect in their tumors, found in only 5-10% of rectal cancers, but it suggested this approach might work. The backstory of the rectal cancer patients was reported in STATnews, and the NEJM editorial is here.
Through incremental progress, the overall death rate from colorectal cancer has dropped 40%, but it has taken 50 years. By 2019, some of the same Memorial Sloan Kettering group reported an overall survival of 73% at 5 years in localized rectal patients (lower stage patients). To achieve even that level, patients needed significant chemo and radiation, reported in the context of a study to determine the optimal timing of major surgery.
The point is, for AD / dementia therapy, that rectal cancer therapy took decades to develop increments of progress, refine chemo combinations (like the FOLFOX regimen, etc), refine radiation to delicate areas like the pelvis, and refine surgical techniques. Along the way, countless lives have been extended. A substantial number still have serious quality of life issues and too many still don’t respond or survive, which should not be minimized.
Here’s the big thing about the new report: the dostarlimab agent is not “chemo”, it optimizes cancer cell clearance through a person’s own immune system! It’s an “immune checkpoint inhibitor (ICI).” The mechanism of action doesn’t involve the cancer cell directly [AlzGadfly in his oncology days did prescribe an ICI, before his AD caregiver days. ] A 2022 historical review of ICIs:
So it took 18 years from a mouse anti-tumor effect to first-in-class FDA approval for ipilimumab in 2014. For PD1 agents, it was only 2 years from mouse results to human trials, then another 7 years for FDA approval. All agents showed survival benefits in Phase 3 trials. For ipilimumab, the benefit was not apparent for 18-24 months, and then it was only 10%, but it seemed fairly durable. Two Nobel Prizes given for work in this arena.
But now there may be a whole new class of agents for a few patients, if the durability holds up. One has to be careful since a number of pediatric cancers like neuroblastoma and lymphoma can respond, only to come roaring back as resistant relapses. The patients may then require more drastic therapy like marrow ablative chemo with hematopoietic stem cell support. The other implied point is that the oncology clinical approach is aggressive.
Many of the AD /dementia trials over the last several years seem to be proprietary single agent Pharma trials. Very few, if any, innovative combination trials are listed. On ClinicalTrials.gov July 29, 2022 (today) there are 95 trials in the US actively recruiting, Phase 1,2,3 for interventions in Dementia or Alzheimers. Many are for symptoms like sleep or agitation issues. The same search filters for colorectal cancer yields 253 trials. Colorectal cancer is said by ACS to have about 45,000 new cases per year; Alzheimer’s is said by the Alz Assn to have 500,000 new cases per year.
Cancer therapeutics has some success in the brain, but hit the wall for others; the approach will be one of the topics for Part II, to be posted next month.