Periodontitis influence on the outcome of immunotherapy targeting CTLA-4

Chemotherapy, radiotherapy and surgery were the triad of cancer treatment in older ages. In 1890, the invention of Cooley, reporting the utilization of immune-stimulation in solid untreatable tumors, has revolutionized the cancer therapy. This particular treatment modality has been elaborated as immunotherapy. Ever since the introduction of immunotherapy, an intricate research has been carried out for decades which ultimately landed in targeting T cells. The conserved negative regulators of T cell activation are the primary targets of immunotherapy current date.

Cytotoxic T Lymphocyte Associated protein 4 (CTLA-4) was found to be an important co-stimulatory molecule of T cells, similar to Cluster of Differentiation 28 (CD28) (BOX1). CTLA-4 was proven to be inhibiting the activation and proliferation of T cells by multiple mechanisms i.e., by antagonizing the activity of CD28, by competitive inhibition of co-stimulatory ligands, prevention of immune conjugates and recruit inhibitory effectors.

Combatively, CTLA-4 was considered an important “immune checkpoint molecule” and targeted for blockade in the treatment of cancer. James Allison and colleagues first invented that neutralizing anti-CTLA-4 antibodies had reported to elevate anti-tumoral immunity. In this core, a range of immunotherapy agents such as ipilimumab , tremulimumab, etc., are invented and invocated as a recommended primary care regimen for various cancers like melanoma, urothelial cancers, etc.,.

Despite the dynamics, various systemic inflammatory burdening conditions have been supposedly hypothesized to have a detrimental effect on immunotherapy outcomes. One such profound systemic inflammatory burden, affecting or having an impact on various systemic conditions is reportedly periodontitis. Periodontitis is a chronic immunoinflammatory condition incited by microbial origin. Dysbiosis is proven to be the key to trigger the inflammation cascade, leading to adverse profile of various inflammatory marker. To specific note on the area of research, Porphyromonas gingivalis, a keystone pathogen, has been proven in multitude to trigger an imbalance in systemic immunoinflammatory burden. The virulence factors of the microbe, specifically gingipains, Outer Membrane protein are said to trigger a wide array of molecular agent and one such key molecule is CTLA-4. Various literature evidence supports the elevation of CTLA-4 in the progression of periodontitis.

The systems biology model of periodontitis dictate the impact of systemic inflammatory profile on local condition and vice versa. By narrowing down the window of research, this local elevation of CTLA-4 in response to periodontitis, can supposedly elevate the systemic CTLA-4 profile. In patients undergoing cancer immunotherapy, this elevation could lead to compromised therapeutic outcomes of the immunotherapy drug.

However, this particular hypothesis despite being proposed theoretically, and reported as reviews, is not proven clinically. This throws an area of quench for evidences, despite the current period is an era of immunotherapy. Thus the current study is a first of its kind, to evaluate the confounding effect of periodontitis related elevation of CTLA-4 levels in the therapeutic outcomes in patients undergoing immunotherapy.

Aim: To evaluate the cofounding effect of elevated CTLA-4 in response to periodontitis on the altered therapeutic outcomes of cancer immunotherapy targeting CTLA-4

Null hypothesis: The levels of CTLA-4 reduction will not differ in cancer patients with and without periodontitis, being treated with anti-CTLA-4 immunotherpy.

Alternate hypothesis : The levels of CTLA-4 reduction will be better in cancer patient who are periodontally healthy and undergoing anti CTLA-4 immunotherapy, when compared to those with periodontitis.