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A recent case report demonstrated that adoptive T-cell transfer targeting the KRAS G12D mutation in a metastatic colorectal cancer patient induced tumour regression . This promising result showed in a clinical setting that T cells are capable of targeting and eliminating colon tumour cells expressing KRAS G12D mutant peptides complexed with major histocompatibility complex (MHC) I proteins at their cell surface. It has implications for all cancers with prevalent mutant KRAS expression. In the most common form of pancreatic cancer PDAC, KRAS is mutated in up to 90% of cases.
Two companies Targovax and GlobeImmune are developing vaccines that contain KRAS mutant peptides for patients with pancreatic cancer. These vaccines involve injection of the peptides and subsequent in vivo generation of a T-cell response against the pancreatic cancer. Targovax’s lead RAS vaccine is called TG01. The company reported that the phase I part of a Phase I/II trial of TG01 and gemcitabine for patients with resected adenocarcinoma of the pancreas  demonstrated that TG01 induced immune responses in 92% of patients. Interim survival data showed that 14 out of 15 evaluable patients were still alive after one year. Safety and tolerability were demonstrated.
GlobeImmune’s product is clinically more advanced with efficacy shown in a subset of pancreatic pancreatic cancer patients in a phase II clinical trial (see here). A companion MALDI-TOF mass spectrometry diagnostic has been developed to predict which pancreatic cancer patient are most likely to benefit from the vaccine based on their tumours protein expression profile.
As was demonstrated by GlobeImmune’s phase II trial not all pancreatic cancer patients with KRAS mutations are guaranteed to benefit. This is most likely due to pancreatic cancer’s “cold” immunoscore (see here). KRAS vaccine combination strategies with agents that improve pancreatic cancer’s immunoscore will likely increase the number patients who respond to mutant RAS vaccines.
- Tran E, Robbins PF, Lu Y-C, et al. T-cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med 2016;375:2255-2262. DOI: 10.1056/NEJMoa1609279.
- ClinicalTrials.gov Identifier: NCT02261714 – Antigen-specific Cancer Immunotherapy (TG01) and Gemcitabine as Adjuvant Therapy in Resected Pancreatic Cancer.
Immunoscore is a measure of the presence of activated immune cells within a tumour as defined by the Union Internationale Contre le Cancer . Immune checkpoint inhibitors are generally not effective against tumours with a low mutational burden and low (“cold”) immunoscores. By contrast tumours such as melanoma for which immune checkpoint inhibitors are highly effective have a high (“hot”) immunoscore.
Pancreatic cancer and other solid tumours have been described to have a “cold” immunoscore which correlates with the failure of immune checkpoint inhibitors to be effective . In addition a “cold” or actively immunosuppressive solid tumour microenvironment also inhibits the mechanism of action of the class of immunotherapeutics known as CAR-T which are effective for haematological cancers.
Understanding the molecular basis of the “cold” pancreatic cancer immunoscore and developing agents that can “heat-up” pancreatic cancer is essential in order to manufacture effective immunotherapeutic treatments for this disease.
- Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C, Lugli A, Zlobec I, Hartmann A, Bifulco C, Nagtegaal ID, Palmqvist R, Masucci GV, Botti G, Tatangelo F, Delrio P, Maio M, Laghi L, Grizzi F, Asslaber M, D’Arrigo C, Vidal-Vanaclocha F, Zavadova E, Chouchane L, Ohashi PS, Hafezi-Bakhtiari S, Wouters BG, Roehrl M, Nguyen L, Kawakami Y, Hazama S, Okuno K, Ogino S, Gibbs P, Waring P, Sato N, Torigoe T, Itoh K, Patel PS, Shukla SN, Wang Y, Kopetz S, Sinicrope FA, Scripcariu V, Ascierto PA, Marincola FM, Fox BA, Pagès F. Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours. J Pathol. 2014 Jan;232(2):199-209. doi: 10.1002/path.4287. Review. PubMed PMID: 24122236.
Heat killed Mycobacterium obuense is claimed to stimulate Th1 immune response against tumours and down regulate Th2 responses . It acts as a Pathogen-Associated Molecular Pattern (PAMP) acting on γδ T-cells, granulocytes, and antigen-presenting cells (such as dendritic cells) [2, 3]. Intradermally delivered Mycobacterium obuense has recently undergone a phase II clinical trial in advanced pancreatic cancer patients demonstrating safety and showed promising signs of efficacy that need to be confirmed in a phase III clincal trial . A systemic immune activation against pancreatic cancer is promising as these tumours are difficult for the clinician to manipulate/ manually inject.
- Charles Akle Satvinder Mudan John Grange (2013). Cancer therapy, US patent US13396866 , 2013-12-31 .
- Fowler DW, Copier J, Wilson N, Dalgleish AG, Bodman-Smith MD. Mycobacteria activate γδ T-cell anti-tumour responses via cytokines from type 1 myeloid dendritic cells: a mechanism of action for cancer immunotherapy. Cancer Immunol Immunother. 2012 Apr;61(4):535-47. doi: 10.1007/s00262-011-1121-4. PubMed PMID: 22002242.
- Bazzi S, Modjtahedi H, Mudan S, Akle C, Bahr GM. Analysis of the immunomodulatory properties of two heat-killed mycobacterial preparations in a human whole blood model. Immunobiology. 2015 Dec;220(12):1293-304. doi: 10.1016/j.imbio.2015.07.015. PubMed PMID: 26253276.
- Dalgleish AG, Stebbing J, Adamson DJ, Arif SS, Bidoli P, Chang D, Cheeseman S, Diaz-Beveridge R, Fernandez-Martos C, Glynne-Jones R, Granetto C, Massuti B, McAdam K, McDermott R, Martín AJ, Papamichael D, Pazo-Cid R, Vieitez JM, Zaniboni A, Carroll KJ, Wagle S, Gaya A, Mudan SS. Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer. Br J Cancer. 2016 Sep 27;115(7):789-96. doi: 10.1038/bjc.2016.271. PubMed PMID: 27599039