Checkpoint inhibitor therapy & Resistance Mechanisms

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.[1] The first anti-cancer drug targeting an immune checkpoint was ipilimumab, a CTLA4 blocker approved in the United States in 2011.[2]

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.[3][4]

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.[5]

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.[6][7]

The first checkpoint antibody approved by the FDA was ipilimumab, approved in 2011 for treatment of melanoma.[2] 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.[8][9]

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.[10]

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.[11]

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.[11]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,

 Clinical Trials

Initial clinical trial results with IgG4 PD1 antibody Nivolumab (under the brand name Opdivo and developed by Bristol-Myers Squibb) were published in 2010.[1] 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.[12]

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.[13] Keytruda is approved to treat melanoma and lung cancer and is produced by Merck.[12]

Spartalizumab (PDR001) is a PD-1 inhibitor currently being developed by Novartis to treat both solid tumors and lymphomas [14] [15] [16]

 PD-L1 inhibitor

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.[17]

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

Chronologically determined
Name Target Approved
Ipilimumab CTLA-4 2011
Nivolumab PD-1 2014
Pembrolizumab PD-1 2014
Atezolizumab PD-L1 2016
Avelumab PD-L1 2017
Durvalumab PD-L1 2017
Cemiplimab PD-1 2018

Text under construction

References

  1.  Pardoll DM (March 2012). “The blockade of immune checkpoints in cancer immunotherapy”. Nature Reviews. Cancer. 12 (4): 252–64. doi:10.1038/nrc3239. PMC 4856023. PMID 22437870.
  2.  Cameron F, Whiteside G, Perry C (May 2011). “Ipilimumab: first global approval”. Drugs. 71 (8): 1093–104. doi:10.2165/11594010-000000000-00000. PMID 21668044.
  3. ^ Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ (July 2007). “Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses”. Immunity. 27 (1): 111–22. doi:10.1016/j.immuni.2007.05.016. PMC 2707944. PMID 17629517.
  4. ^ Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M, Escors D (October 2011). “PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells”. EMBO Molecular Medicine. 3 (10): 581–92. doi:10.1002/emmm.201100165. PMC 3191120. PMID 21739608.
  5. ^ Syn, Nicholas L; Teng, Michele W L; Mok, Tony S K; Soo, Ross A (2017). “De-novo and acquired resistance to immune checkpoint targeting”. The Lancet Oncology. 18 (12): e731–e741. doi:10.1016/s1470-2045(17)30607-1. PMID 29208439.
  6. ^ “2014 Tang Prize in Biopharmaceutical Science”. Retrieved 2016-06-18.
  7. ^ Devlin, Hannah (2018-10-01). “James P Allison and Tasuku Honjo win Nobel prize for medicine”. the Guardian. Retrieved 2018-10-01.
  8. ^ Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M (June 2012). “Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study”. Journal of Clinical Oncology. 30 (17): 2046–54. doi:10.1200/JCO.2011.38.4032. PMID 22547592.
  9. ^ Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, Zheng L, Diaz LA, Donehower RC, Jaffee EM, Laheru DA (September 2013). “Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer”. Journal of Immunotherapy. 36 (7): 382–9. doi:10.1097/CJI.0b013e31829fb7a2. PMC 3779664. PMID 23924790.
  10. ^ Postow MA, Callahan MK, Wolchok JD (June 2015). “Immune Checkpoint Blockade in Cancer Therapy”. Journal of Clinical Oncology. 33 (17): 1974–82. doi:10.1200/JCO.2014.59.4358. PMC 4980573. PMID 25605845.
  11. ^ Jump up to: a b van Hooren L, Sandin LC, Moskalev I, Ellmark P, Dimberg A, Black P, Tötterman TH, Mangsbo SM (February 2017). “Local checkpoint inhibition of CTLA-4 as a monotherapy or in combination with anti-PD1 prevents the growth of murine bladder cancer”. European Journal of Immunology. 47 (2): 385–393. doi:10.1002/eji.201646583. PMID 27873300.
  12. Pollack A (2016-05-18). “F.D.A. Approves an Immunotherapy Drug for Bladder Cancer”. The New York Times. ISSN 0362-4331. Retrieved 2016-05-21.
  13. ^ “Enrolling the immune system in the fight against cancer”. The Economist. Retrieved 2017-10-01.
  14. ^ World Health Organization (2017). “International Nonproprietary Names for Pharmaceutical Substances (INN)” (PDF). WHO Drug Information. 31 (2).
  15. ^ Immuno-Oncology News. “PDR001″.
  16. ^ National Cancer Institute. “NCI Drug Dictionary”.
  17. ^ Postow, Michael A.; Sidlow, Robert; Hellmann, Matthew D. (10 January 2018). “Immune-Related Adverse Events Associated with Immune Checkpoint Blockade”. New England Journal of Medicine. 378 (2): 158–168. doi:10.1056/nejmra1703481. PMID 29320654.Screen Shot 2015-04-24 at 5.34.39 PM

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