TO WHAT EXTENT WILL IMMUNOTHERAPY LEAD THE WAY IN THE BATTLE AGAINST PANCREATIC CANCER?

Pancreatic cancer is one of the deadliest diseases to befall modern day society. [1] With less than 1% of patients surviving after 10 years in England and Wales in 2010-11, with less than 5% surviving after 5 years of being diagnosed. There has, however, been some progress in recent years, with an increase in the one-year survival rate to around 13% [2].  Traditional methods such as the chemotherapy drug Gemcitabine have been the ‘gold standard’ of treatment against pancreatic cancer, with the most successful method being oncological surgery – which includes the removal of all or some parts of the pancreas including healthy tissue, in order to achieve ‘clear margins’ which means that there are no cancer cells in the edges of the healthy tissue removed. However, only about 20% of patients [3] with pancreatic cancer are able to have surgery because most pancreatic cancers are first diagnosed when the disease has already spread – at stage IV.  The novel potential treatment of immunotherapy has recently been introduced within the medical realm, and in this dissertation, I will aim to discuss and conclude a judgement on various potential therapies that can have the most successful impact on pancreatic cancer, as well as taking into account the consequential effects on patients’ lives.

Upon recent times, due to the drought of success with surgical resections of pancreatic adenocarcinomas (PACs), neoadjuvant therapy has been analysed and suggested as the best current form of treatment method by Dr. Belli and her clinical team. [4] Their reasoning is due to the fact that current evidence from clinical trials and studies conducted suggest R0 / negative margin rates have been more successful with the advent of chemotherapy drugs – normally chosen between the two most active combination regimens for metastatic disease, namely modified FOLFIRNOX and gemcitabine/nab-paclitaxel. Their rationale behind their medical opinion is that surgical resection rates increase, giving a yield of 68% for BR pancreatic tumours and 36% for LA pancreatic tumours.  In an effort to not only improve surgical resection rates, but to also : downstage disease and  decrease surgical complexity – especially where the primary procedure of Pancreaticoduodenectomy, developed by Allen Whipple at Columbia University, performed for patients with resectable tumours of the pancreatic head, where over 65% of pancreatic cancer is discovered [5], is such a technically challenging operation, given the proximity of the pancreas to major vascular structures, and it carries substantial operative and postoperative risks. Unfortunately, even with a successful R0 resection (pathologically negative margin), neither pancreaticoduodenectomy nor distal pancreatectomy, can guarantee a cure and rates of recurrence approach 80% [6]. As well as this, Dr. Belli and her team uphold a medical gravitas that all patients must receive chemotherapy. As well as to treat locally invasive disease before resection, as surgery may alter perfusion in the area, and treat micrometastatic disease earlier, at the time of diagnosis.

In 2017, Mokdad et al published a unique retrospective study implementing propensity score matched analysis to investigate the role of neoadjuvant therapy in patients with early stage pancreas cancer. The authors queried the National Cancer Database for patients with stage I or II PDAC who underwent surgery between 2006 and 2012. A total of 2,005 patients treated with neoadjuvant therapy followed by surgery were matched with 6,015 patients who underwent upfront resection and the authors reported a median overall survival difference of 5 months (26 v 21 months) favouring those who received neoadjuvant therapy. Such data, bases the medical view of neoadjuvant therapy being the most suitable and viable treatment at this current moment in time.

However, looking at the Mokdad study, it was limited due to a selection bias as the neoadjuvant therapy group was populated with only those patients who tolerated neoadjuvant therapy, although, it still demonstrates the utility of neoadjuvant therapy as a selection strategy for management of patients with early stage disease. Dr. Belli and her team go on to justify the use of common preferred regimens such as modified FOLFIRNOX, which initially validated by Conroy et al, who in 2011 published their landmark findings of a median survival of 11.1 months compared to 6.8 months with gemcitabine alone.

Assessing the source, there was a conflict of interest with Dr. Manji, who had received research funding for a clinical trial from Plexxikon, MERCK, Roche/ Genentech. This may have suggested conformational bias occurring within the clinical team, however, overall this does not hinder the fact that the date presented to support Dr.Belli’s opinions were to an appreciative level, such that the source can be considered reliable.

Pancreatic cancers contain exclusively tumorigenic cancer stem cells (CSCs), which are highly resistant to chemotherapy, resulting in a relative increase in CSC numbers during gemcitabine treatment. Another source from Dr. Mueller [7] and her clinical research team express the view of a potential breakthrough of a novel therapeutic treatment to this disease with such ‘devastating prognostics’. This is through the use of combined target treatment – through combining cyclopamine, rapamycin – which are cell-signalling pathway inhibitors to tumorigenic CSCs, mixed with chemotherapy drugs like Gemcitabine, allowing for the sonic hedgehog pathway to be blocked as well as signalling blockades for mTOR – Only the combined inhibition of both pathways together with chemotherapy reduced the number of CSCs to virtually undetectable levels in vitro and in vivo. Most importantly, in vivo administration of this triple combination in mice with established patient-derived pancreatic tumours was reasonably tolerated and translated into significantly prolonged long-term survival.

The source possesses no conflicts of interest, and its origins are supported by the provenance of more than 10 clinical researchers, as well as the publishment being featured in reputable Gastroenterology Medical Volumes.

The advent of Immunotherapy is fairly new to the pancreatic cancer treatment globe, with traditional methods such as chemotherapy, radiotherapy and oncological surgery around in the 20th century. However, with potential novel techniques arising in the form of targeted therapies and gene therapies, Immunotherapy is an individual aspect to the battle against Pancreatic Cancer – or simply put, ‘a Knight on the Chessboard’.

Immunotherapies that target cytotoxic T lymphocyte antigen-4, programmed cell death protein-1, and programmed death-ligand 1 checkpoints have shown remarkable activities in several cancers such as melanoma, renal cell carcinoma, and non-small cell lung cancer due to high numbers of somatic mutations, combined with cytotoxic T-cell responses. However, single checkpoint blockade was ineffective in pancreatic cancer, highlighting the challenges including the poor antigenicity, a dense desmoplastic stroma, and a largely immunosuppressive microenvironment. Hence, combining immune checkpoint therapies with other treatment modalities such as chemotherapy, radiotherapy, and targeted therapy are of pursuit. These combination therapies hold promise in unleashing the potential of immunotherapy in pancreatic cancer to achieve better and more durable clinical responses by enhancing cytotoxic T-cell responses.

Unprecedented clinical success has been observed for therapies targeting two major checkpoints of T cell: Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1). Both checkpoints are expressed on activated T cells, but they act in distinct pathways. CTLA-4 blocks the essential cluster differentiation 28 (CD28) costimulation by competing and depleting the ligand of CD28 (B7-1 and B7-2) on antigen presenting cells (APCs). On the other hand, PD-1 interferes with the signalling pathways mediated by the T cell receptor and serves as a more distal block of T cell response by binding to its ligands (programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2) which are present on many cell types including tumours cells. Hence, the activity of CTLA-4 and PD-L1 inhibitors are being explored in pancreatic cancer as well.

However, in early clinical trials single agent therapy with anti-CTLA-4 or anti-PD-1/anti-PD-1 pathway (anti-PD-L1) alone were largely ineffective in pancreatic cancer [8]. In a single-arm phase II study, lpilimumab (anti-CTLA-4) failed to induce tumour response in patients with advanced pancreatic cancer. This shows lack of efficacy in Immunotherapy in the battle against Pancreatic Cancer as of yet.  This efficacy, has been diagnosed as handicapped by small numbers of cumulative mutational load – which can lead to the expression of non-self antigens also known as ‘neo-antigens’. Cancers with higher number of mutational load are associated with more neoantigens that are easier to be recognized by the immune system, compared to cancer with lower number of mutational load.  There are 3 hurdles to Pancreatic Immunotherapy.

Firstly, the mutational load in pancreatic cancer is very low as compared with melanoma and lung cancers – hence less neoantigens ; thus less cancer cells identified as foreign and go ‘undetected’ within the body. Second, pancreatic cancer features a largely immunosuppressive microenvironment, characterized by a dense desmoplastic reaction with prominent infiltration of tumorigenic macrophages and myeloid derived suppressor cells. Finally, there are very few infiltrating T cells in the microenvironment of pancreatic cancer, therefore could not provide sufficient T cell responses. Pancreatic cancer creates a nonimmunogenic (or “cold”) tumour microenvironment, limiting the activity of immune checkpoint therapies that were previously discussed.

In order to overcome these hurdles, one would need to combine such a therapy with one that can initiate a ‘hot’ microenvironment. First, therapies that enhance tumour antigen presentation to help T cell priming/activation; second, therapies that modulate tumour microenvironment to relieve immunosuppression. Third, therapies which breakdown the desmoplastic barrier surrounding pancreatic cancer to bring infiltrating T cells.

Such combined therapies, novel adjuvant therapies, are in the clinical trial stage at this moment in time, thus, we are limited as to the observations that can be made. Immune checkpoint therapy combined with chemotherapy (Gemcitabine), radiotherapy or Cancer Vaccines is being implemented for enhancing T-cell activation.  Radiotherapy and Inhibitors are used in conjunction for targeting the immunosuppressive microenvironment. As well as PEGPH20 enzymes being used to hydrolyse the desmoplastic barrier.

Both challenges and opportunities exist for the development of effective immunotherapy for pancreatic cancer. Given that single agent therapies against CLTA-4 or PD-1 or PD-L1 immune checkpoint were largely ineffective in pancreatic cancer, ongoing investigations and future directions lie in the field of combination therapies, where additional treatment modalities may cause durable anti-tumour immune responses by enhancing tumour-specific T cell activation and opposing the immunosuppressive microenvironment in pancreatic cancer.

In conclusion, Individualised Immunotherapy treatment for Pancreatic Cancer is a distant future in relation to alternative novel techniques such as adjuvant therapy, with key successors being Chemotherapy in conjunction with Immune Checkpoint therapy – in order to enhance T-cell activation and increase cytotoxicity and efficacy of cancer cell death, as well as cell-signalling pathway inhibitors in conjunct with Immune Checkpoint therapy in order to control and antagonize the immunosuppressive microenvironment. These such Trial-phased treatments are most likely to be FDA approved in the future, as more success with each trial arises. The world of pancreatic cancer treatment is multi-faceted, with alternative forms of treatment also being researched and trialled such as Gene therapies. [9] One example of this is the Soluble TRAIL Armed Human MSC. Here adipose mesenchymal stromal/stem cells (AD-MSC) have been armed to constantly release a soluble trimeric and multimeric variant of the known anti-cancer TNF-related apoptosis-inducing ligand (sTRAIL). This cancer gene therapy strategy was in vitro challenged demonstrating that sTRAIL was thermally stable and able to induce apoptosis in the PDAC lines BxPC-3, MIA PaCa-2 and against primary PDAC cells. sTRAIL released by AD-MSC relocated into the tumour stroma was able to significantly counteract tumour growth in vivo with a significant reduction in tumour size, in cytokeratin-7+ cells and by an anti-angiogenic effect. These results indicate that adipose MSC can very efficiently vehicle a novel TRAIL variant opening unexplored opportunities for PDAC treatment. Having only scraped the surface of the potential therapies currently being researched or trialled, it is impossible to say with certainty that Immunotherapy alone is the way forward. However, in this dissertation, I have aimed to determine whether Immunotherapy will lead the way forward, but I cannot confirm with certainty, merely, hypothesize that adjuvant immunotherapy is most probably a step forward in the right direction – away from the aforementioned treatment methods in my review of literature, which included neo-adjuvant therapy as well as targeted molecular therapy, which do not satisfy the progression needed by thousands of patients globally, that are faced with poor prognostic statistics till this day.

Bibliography:

  1. Cancer Research UK, C. (2019). Pancreatic cancer statistics. [online] Cancer Research UK. Available at: https://www.cancerresearchuk.org/health-professional/cancer-

Statistics/statistics-by-cancer-type/pancreatic-cancer#heading-Two [Accessed 3 Apr. 2019].

  1. Williamson, S. and Todd, A. (2019). Current advances and research in the treatment of pancreatic cancer. [online] Pharmaceutical Journal. Available at: https://www.pharmaceutical-journal.com/opinion/comment/current-advances-and-research-in-the-treatment-of-pancreatic-cancer/10994778.article? [Accessed 3 Apr. 2019].
  2. net editorial board, C. (2019). Pancreatic Cancer – Types of Treatment. [online] Cancer.Net. Available at: https://www.cancer.net/cancer-types/pancreatic-cancer/types-treatment [Accessed 3 Apr. 2019].
  3. Belli, C., Cereda, S., Anand, S. and Reni, M. (2013). Neoadjuvant therapy in resectable pancreatic cancer: A critical review. Cancer Treatment Reviews, 39(5), pp.518-524.
  4. T. Greenlee, T. Murray, S. Bolden, P.A. Wingo (2000). Cancer Statistics. CA, 50 (1), pp. 7-33
  5. Kleeff, M. Korc, M. Apte, et al (2016). Pancreatic cancer. Nat Rev Dis Primers, 2, p. 16022
  6. Mueller, M., Hermann, P., Witthauer, J., Rubio–Viqueira, B., Leicht, S., Huber, S., Ellwart, J., Mustafa, M., Bartenstein, P., D’Haese, J., Schoenberg, M., Berger, F., Jauch, K., Hidalgo, M. and Heeschen, C. (2009). Combined Targeted Treatment to Eliminate Tumorigenic Cancer Stem Cells in Human Pancreatic Cancer. Gastroenterology, 137(3), pp.1102-1113.
  7. Winograd R, Byrne KT, Evans RA, Odorizzi PM, Meyer AR, Bajor DL, Clendenin C, Stanger BZ, Furth EE, Wherry EJ, Vonderheide RH. (2015) Cancer Immunol Res. Apr; 3(4):399-411.
  8. Spano, C., Grisendi, G., Golinelli, G., Rossignoli, F., Prapa, M., Bestagno, M., Candini, O., Petrachi, T., Recchia, A., Miselli, F., Rovesti, G., Orsi, G., Maiorana, A., Manni, P., Veronesi, E., Piccinno, M., Murgia, A., Pinelli, M., Horwitz, E., Cascinu, S., Conte, P. and Dominici, M. (2019). Soluble TRAIL Armed Human MSC As Gene Therapy For Pancreatic Cancer. Scientific Reports, 9(1).

Photo Credits due to: https://immuno-oncologynews.com/2015/12/11/4-new-blood-cancer-trials-readying-test-immunotherapy-drug/

Danyal Mahmood