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Immune Checkpoints: New Promises in Cancer Treatment

Posted on October 26th, 2016 by in Pharma R&D

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Cancer immunotherapy (especially checkpoint inhibitors) is hot in the cancer therapeutics world, but we are still learning about how best to use them and in which patients. The current explosion in new cancer immunotherapies relates to braking T-cell activation: checkpoint therapies. Jim Allison’s group (ref 1) is credited with first demonstrating that anti-CTLA-4 (i.e. braking) could boost anti-tumor response of T-cells, showing that immune checkpoint blocking is therapeutically relevant.

There are various types of cancer immunotherapy approaches. Here is a short list of them (ref 2):

  1. Immune checkpoint – Stops the brakes (i.e. checkpoint proteins) on T-cell activation, which would limit the duration and extent of immune activation.
  2. Adoptive cellular – Manipulation of T-cells to enhance tumor-killing activation.
  3. Therapeutic antibodies – Engineered antibodies directed at specific tumor types.
  4. Vaccines – Use patient’s tumor cells in a vaccine / adjuvant system, employing the patient’s immune response.
  5. Immune modulators – Cytokines and growth factor proteins used to enhance immune response.

Checkpoint inhibitor interest started with iplimumab (Yervoy), which is an antibody directed to the CTLA4 receptor, an important inhibitory regulator of T-cell activation. More recently, the drugs Opdivo and Keytruda have received a lot of attention – they are checkpoint inhibitors that are mediated by Program Cell Death pathways. Keytruda received breakthrough therapy status by the FDA in 2014 for the treatment of NSCLC.

Program Cell Pathways (PD-L1, PD-1) are pathways used by Opdivo (nivolumab) and Keytruda (pembrolizumab). PD-L1 expression diagnostics are also attention getters because these assays are used to select patients for therapy and clinical trials. PD-L1 is found on various cell types, and the definition of a positive test is debatable. The FDA has approved two PD-1 monoclonal antibody drugs against cancer, as well as a monoclonal antibody for PD-L1, although these assays have pretty liberal ranges for the cutoff for positivity. Because these kits use different antibodies, results can be inconsistent. Adding to the complexity, tumor heterogeneity and spontaneous mutations occur, so arriving at a cutoff definition for a positive result is very debatable (ref 3). Future work is now trying to develop blood-based biomarkers for PD-1 and PD-L1, which would be welcomed by the clinical oncology community. The diagnostic sector is seeing much opportunity in developing and having approved PD-1 or PD-L1 assay as a companion to the therapeutic.

There are high stakes with optimizing patient selection and biomarkers in clinical trials for checkpoint inhibitors. Opdivo and Keytruda are in direct competition with each other for non-small cell lung cancer (NSCLC) as second line therapy; that is, patients must first fail conventional therapy before being prescribed these drugs (ref 4). Merck and BMS see a pot of gold at the end of the rainbow if they could obtain first-line therapy status. Merck recently demonstrated good efficacy in patients who were positive for the PD-L1 biomarker. BMS’s approach was to take all comers into their trial, choosing not to use the precision medicine approach in selecting “the right patients.” Unfortunately, BMS recently reported a failed trial.

Developing immunotherapeutics has differences to a small molecule and there is much to learn and optimize. Choosing patients for trials is especially complex, with patients and tumors showing heterogeneity. One major source of heterogeneity are the somatic tumor mutations which are influenced by environmental factors, including the diet, age, and microbiome. Once we learn more about the heterogeneity, high responding patients can be more easily identified.  Another area of challenge is finding the right starting dose and regimen. Fortunately, there is a lot of new exciting quantitative systems modeling which will help define the optimum dose range and regimen based on the animal to human translation and individualized for the patient.  Finally, management of immune-related severe adverse events (irAE) is a challenge as we are dealing with host T-cell immune responses. More understanding of long-term effects and how to manage the toxicities will be needed to allow these drugs to be used on a more wide-spread basis in the clinic (ref 3).

References:

  1. Krummel MF, Allison JP (1995). “CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation”. Exp. Med. 182 (2): 459–65.
  2. McCune, JS (2016). “Immunotherapy to Treat Cancer”; Clin.Pharm.Ther; 100(3): 198-203.
  3. Mansfield AS, Dong H. “Implications of Programmed Cell Death 1 Ligand 1 Heterogeneity in the Selection of Patients With Non-Small Cell Lung Cancer to Receive Immunotherapy.” Clin.Pharm.Ther; 100(3): 220-222.
  4. http://www.forbes.com/sites/johnlamattina/2016/08/08/bristol-myers-high-risk-opdivo-lung-cancer-study-shows-challenges-of-clinical-trials/#76cba41f9f7e

For more information on how Pathway Studio can help with cancer therapeutics, click here.


 

All opinions shared in this post are the author’s own.

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