-Lakshmanan Jagannathan

Everyone is familiar with the classic action movie storyline, where in, the greedy agent turns hostile and tries to destroy the system from within. He uses his knowledge of the system to his favour and allies with other rogue elements in the system. Then comes the selfless protagonist, who is usually unnoticed and underappreciated for his good work in protecting the agency. With the help of some new allies, the hero eliminates the rogue agent(s) and continues to do his menial job. This analogy holds good for cancer and immunotherapy. The greedy rogue agent being cancer, who escapes immune surveillance by subverting the body’s defence mechanisms, similar to the rogue agent who uses allies to destroy the system. The unsung hero is the immune system and immunotherapy is the new-found ally of the immune system.

Though the concept of using body’s own immune system to fight against cancer is very old (e.g., Il-2 therapy was approved for cancer in year 1983, For more details on the history of cancer immunotherapy check:- http://www.nature.com/nrd/journal/v10/n8/fig_tab/nrd3500_I1.html). However, it was not properly exploited until the recent discovery of immune check point pathways (PD-1, CTLA4, and TIGIT). Cancer cells use these -the body’s internal immune regulatory mechanisms to effectively subvert the cytotoxic activities of T cells (CD8+ T cells). Immunotherapeutic agents that target combinations of these pathways (e.g., PD-1 and CTLA4) are especially promising.  Unsurprisingly, FDA has approved Ipilimumab (Yervoy), Nivolumab (Opdivo) from BMS and Pembrolizumab (Keytruda) from Merck under special category of Breakthrough Therapy Designation Approvals for the treatment of highly aggressive forms of solid tumours including melanoma and/or lung cancer. Ipilimumab targets CTLA4 while Nivolumab and Pembrolizumab target PD1-PDL1 pathway. These therapies showed higher overall survival/response rate with minimal adverse reaction profile leading to rapid approvals from FDA. A quick look at clincaltrial.gov (Nivolumab, Ipilimumab, Pembrolizumab) revealed a mind boggling number of ongoing clinical trials (Fig. 1; plotted from the data taken from clinicaltrial.gov) involving several types of cancer (Fig. 2, plotted from the data taken from clinicaltrial.gov) being tested with these immune check point inhibitors. This is reason enough to believe that this is going to be the future of cancer therapy.

 

Despite all the success, there are still some limitations and uncertainty surrounding the cancer immunotherapy. Only a subset cancer patients showed good response to check point inhibitors. Also, the association of PDL1 positive cancer patient to therapy response rate has been proved unsuccessful in the recent BMS lung cancer trial. Hence, understanding this phenotype-genotype variation between the responder to non-responder is very crucial. Further, finding perfect combination therapy, dosage regimen, suitable biomarkers are some of the other key areas which will secure the future of cancer immunotherapy.

Building mechanistic models that capture the details of tumor-immune interactions can be used to understand clinical data, test hypotheses and aid in trial design (similar to other therapeutic areas such as metabolism, auto-immune disease, where QSP models are routinely used to support decision making). Existing models of tumour-immune interactions can be leveraged and expanded to include clinically relevant features as well as mechanistic understanding of non-response to therapy.

We will discuss some of the models of the tumour-immune interaction available in the literature in the upcoming blog posts.