Checkpoint inhibitor therapy is a form of cancer immunotherapy currently under research. The therapy targets immune checkpoints, key regulators of the immune system that stimulate or inhibit its actions, which tumors can use to protect themselves from attacks by the immune system. Checkpoint therapy can block inhibitory checkpoints, restoring immune system function. The first anti-cancer drug targeting an immune checkpoint was ipilimumab, a CTLA4 blocker approved in the United States in 2011.
Currently approved checkpoint inhibitors target the molecules CTLA4, PD-1, and PD-L1. PD-1 is the transmembrane programmed cell death 1 protein (also called PDCD1 and CD279), which interacts with PD-L1 (PD-1 ligand 1, or CD274).
PD-L1 on the cell surface binds to PD1 on an immune cell surface, which inhibits immune cell activity.
Among PD-L1 functions is a key regulatory role on T cell activities.
The Lab evidence shows that (cancer-mediated) upregulation of PD-L1 on the cell surface may inhibit T cells that might otherwise attack.
Antibodies that bind to either PD-1 or PD-L1 and therefore block the interaction may allow the T-cells to attack the tumor.
This is in a nutshell the big “breakthrough” of conventional oncology.
The discoveries in basic science allowing checkpoint inhibitor therapies led to James P. Allison and Tasuku Honjo winning the Tang Prize in Biopharmaceutical Science and the Nobel Prize in Physiology or Medicine in 2018.
Melanoma Checkpoint inhibitor
The first checkpoint antibody approved by the FDA was ipilimumab, approved in 2011 for treatment of melanoma. It blocks the immune checkpoint molecule CTLA-4. Clinical trials have also shown some benefits of anti-CTLA-4 therapy on lung cancer or pancreatic cancer, specifically in combination with other drugs.
However, there are Toxic Side Effects
However, patients treated with check-point blockade (specifically CTLA-4 blocking antibodies), or a combination of check-point blocking antibodies, are at high risk of suffering from immune-related adverse events such as dermatologic, gastrointestinal, endocrine, or hepatic autoimmune reactions.
These are most likely due to the breadth of the induced T-cell activation when anti-CTLA-4 antibodies are administered by injection in the blood stream.
Using a mouse model of bladder cancer, researchers have found that a local injection of a low dose anti-CTLA-4 in the tumour area had the same tumour inhibiting capacity as when the antibody was delivered in the blood.
At the same time the levels of circulating antibodies were lower, suggesting that local administration of the anti-CTLA-4 therapy might result in fewer adverse events.. A little like IPT (insuline potentiation therapy), which uses around 10 percent of chemo-agents that tend to stay long in the tumor micro-environment, versus systemic chemo that wipes out nearly every fast growing cell on its path,
Initial clinical trial results with IgG4 PD1 antibody Nivolumab (under the brand name Opdivo and developed by Bristol-Myers Squibb) were published in 2010. It was approved in 2014. Nivolumab is approved to treat melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancer, and Hodgkin’s lymphoma.
Pembrolizumab (brand name Keytruda) is another PD1 inhibitor that was approved by the FDA in 2014 and was the second checkpoint inhibitor approved in the United States. Keytruda is approved to treat melanoma and lung cancer and is produced by Merck.
In May 2016, PD-L1 inhibitor atezolizumab was approved for treating bladder cancer. Other modes of enhancing [adoptive] immunotherapy include targeting so-called intrinsic checkpoint blockades e.g. CISH.
Mechanisms of resistance to immune checkpoint inhibitors
Immunological adverse effects are often caused by checkpoint inhibitors. Altering checkpoint inhibition can have diverse effects on most organ systems of the body. The precise mechanism is unknown, but differs in some respects based on the molecule targeted.
Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have shown unprecedented clinical activity in several types of cancer and are rapidly transforming the practice of medical oncology. Whereas cytotoxic chemotherapy and small molecule inhibitors (‘targeted therapies’) largely act on cancer cells directly, immune checkpoint inhibitors reinvigorate anti-tumour immune responses by disrupting co-inhibitory T-cell signalling.
While resistance routinely develops in patients treated with conventional cancer therapies and targeted therapies, (See File on Conventional Oncology’s limitations), durable responses suggestive of long-lasting immunologic memory are commonly seen in large subsets of patients treated with ICI. So there is hope.
Discussion and Tentative Conclusion
However, initial response appears to be a binary event, with most non-responders to single-agent ICI therapy progressing at a rate consistent with the natural history of disease.
In addition, late relapses are now emerging with longer follow-up of clinical trial populations, suggesting the emergence of acquired resistance.
As robust biomarkers to predict clinical response and/or resistance remain elusive, the mechanisms underlying innate (primary) and acquired (secondary) resistance are largely inferred from pre-clinical studies and correlative clinical data.
Hence, improved understanding and experimentation of molecular and immunologic mechanisms of ICI response (and resistance) are needed. Until there is more success, the ACR Institute prefers its Holistic Immunotherapy.
Pr Joubert (ACR Institute)
Approved Checkpoint Inhibitors
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