Immuno-RT combination - biological basis
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Preclinical evidence supporting immunotherapy-radiotherapy combinations
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Immuno-RT combination - biological basis
- 1. Combining radiation with immunotherapy: Biological basis and clinical applications Dr Balamurugan Vellayappan Consultant Radiation Oncologist Research Director NCIS, NUHS Asst. Professor, NUS
- 2. Disclosures • No relevant financial disclosures • I am no expert in immunology, but I am a believer of immuno-RT combination
- 3. Outline • RT-immuno, immuno-RT synergy • Preclinical evidence about how RT stimulates the immune system • Unanswered questions about how to optimise the relationship
- 4. • Used in cure and palliation. 50% of all cancer patients receive RT Chemo/ targeted/ immuno cEBRT SBRT Surgery Background Local Regional Systemic Single ORR : 20% Combi ORR : 40% Checkmate 25 NEJM 2015 p 1803 Motzer NEJM 2018 p 1277
- 5. Synergistic relationship RT as an immuno-sensitizer Immunotherapy as a radiosensitizer Synergy 1 : RT works as in-situ vaccine to enhance immune control of distant disease (Ab- scopal effect) Synergy 2 : RT induces changes in the TME, allowing for immune- mediated clearance of residual local disease
- 6. A functional immune system is needed for RT to work Stone JNCI 1979
- 7. Immunocompetence is essential for local control Lee Blood 2009 pg 589 20Gy 25Gy
- 8. Ahmed Cancer Imm Res 2013
- 9. Ahmed Cancer Imm Res 2013
- 10. 1.RT increases quantity and novelty of peptide production Reits J Exp Med 2006 p 1259
- 11. Ahmed Cancer Imm Res 2013
- 12. 2.RT primes DC maturation Burnette Cancer Res 2011 p 2488 Gupta J Imm2012 P 558
- 13. Danger signals are dose-dependent Gameiro Oncotarget 2014 p 403
- 14. Ahmed Cancer Imm Res 2013
- 15. 3. RT increases MHC1 expression Reits J Exp Med 2006 p 1259
- 16. Ahmed Cancer Imm Res 2013
- 17. 4. RT increases TILs Sharabi Cancer Imm Res 2015 p 345 Lugade J Imm 2005 p7516 Treg CD8:Treg `
- 18. Zitvogel Nat Imm 2015 p1005
- 19. 5. RT increases tumour PD-L1 expression Deng J Clin Inv 2014 p 687 Tumour cellsMacrophagesMDSCDC
- 20. 6. RT increases Treg activity Liu Am J Cancer Res 2015 p3276 Battaglia IJROBP 2010 p 1546
- 21. Increased TAA release and priming Increased APC maturation Increased MHC 1 expression Enhanced immune cell trafficking (TIL) Increased Treg Increased PDL-1 expression Immuno-enhancer Immuno-suppressor
- 22. Unanswered clinical questions Sequence RT parameters Single or combi immune- checkpoint
- 23. Unanswered clinical questions Sequence RT parameters Single or combi immune- checkpoint
- 24. Best timing? Neo-, concurrent, adjuvant? Young PLOSone 2016 p0157164
- 25. Timing and AGENT matter Young PLOSone 2016 p0157164
- 26. Dovedi Cancer Res 2014 p 5458 Timing and AGENT matter
- 27. Agent Mechanism Suggestion for sequencing Anti-OX40 T-cell co-stimulatory agent Adjuvant CTLA-4 blocker (e.g. ipilimumab) Deplete regulatory T-cells (Treg) within the tumour Neoadjuvant PD-1 blocker (e.g. nivolumab) Competitive inhibitor for PD-1 receptor Concurrent
- 28. Unanswered clinical questions Sequence RT parameters Single or combi immune- checkpoint
- 29. Optimal dose? Dewan Clin Cancer Res 2009 p 5379 Irradiated site Non- Irradiated site 8Gy x 3 + anti CTLA4
- 30. Vanpouille-Box 2017 Nature Comm Fractionation seems better for abscopal effect
- 31. Vanpouille-Box 2017 Nature Comm T-rex is kept low by smaller fractions sizes
- 32. Vanpouille-Box 2017 Nature Comm
- 33. Optimal volume : ENI vs tumour only Marciscano Clin Can Res 2018
- 34. Is particle therapy more immunogenic? Gameiro IJROBP 2016 p 120
- 35. Unanswered clinical questions Sequence RT parameters Single or combi immune- checkpoint
- 36. Checkpoint inhibition : Mono or combo? Victor Nature 2015 p373
- 37. Conclusion • A functioning immune system is required for RT to work • RT can stimulate or suppress the immune system • There is strong pre-clinical evidence to combine RT and immunotherapy • Clinical studies are ongoing to determine the best parameters to enhance the RT-immuno / immuno-RT effect
- 38. • Thank you for your attention ! • Bala_vellayappan@nuhs.edu.sg
Editor's Notes
- In UK – USD 125,000 per QALY with combi (ipi/nivo)
- Corynebacterium parvum, a nonspecific stimulator of the reticuloendothelial system
- B16 syngenic mouse model for melanoma. B16 melanoma is well established to be a highly aggressive, rapidly growing, poorly immunogenic, radio-resistant tumor and also known to resist various treatments, including immunothera- pies One set of mice wild type – functioning immune system. The other type are nude mide (immunocompromised) tumour implanted into flank. RT 20Gy given. Row on top is the tumour on the contralateral side (which was not irradiated) The last colum was in wild type mouse. Where they use anti CD8 antibody
- A schematic view of radiotherapy-induced immune modulations. #1, tumor-associated antigens are released by irradiated dying cancer cells. TAAs and cell debris are engulfed in the tumor microenvironment by phagocytes such as macrophages, neutrophils, and dendritic cells for antigen processing and presentation. #2, radiotherapy-induced cell death releases danger signals, including HSP, HMGB1, and calreticulin (“eat-me” signal for phagocytes). #3, radiotherapy induces increased expression of tumor antigens and MHC class I molecules on tumor cells. #4, radiotherapy-induced T-cell activation increases expression of negative stimulatory molecules such as CTLA-4. #5, certain radiation doses may increase tumor production/secretion of immunosuppressive cytokines such as IL-10 and TGF-β. #6, activated APCs migrate to the draining lymph node, further mature upon encountering TH cells, release IFNs and IL-12/18 to stimulate TH1 responses that support the differentiation and proliferation of antigen-specific CTLs. Activated antigen-specific CTLs traffic systematically from the draining lymph node to infiltrate and lyse primary and distal tumors. RT, radiotherapy.
- A schematic view of radiotherapy-induced immune modulations. #1, tumor-associated antigens are released by irradiated dying cancer cells. TAAs and cell debris are engulfed in the tumor microenvironment by phagocytes such as macrophages, neutrophils, and dendritic cells for antigen processing and presentation. #2, radiotherapy-induced cell death releases danger signals, including HSP, HMGB1, and calreticulin (“eat-me” signal for phagocytes). #3, radiotherapy induces increased expression of tumor antigens and MHC class I molecules on tumor cells. #4, radiotherapy-induced T-cell activation increases expression of negative stimulatory molecules such as CTLA-4. #5, certain radiation doses may increase tumor production/secretion of immunosuppressive cytokines such as IL-10 and TGF-β. #6, activated APCs migrate to the draining lymph node, further mature upon encountering TH cells, release IFNs and IL-12/18 to stimulate TH1 responses that support the differentiation and proliferation of antigen-specific CTLs. Activated antigen-specific CTLs traffic systematically from the draining lymph node to infiltrate and lyse primary and distal tumors. RT, radiotherapy.
- MHC1 allows endogenous proteins to be presented on the surface RT increases the peptide production and display for many days after RT Not only that, it produces NEW peptides that are created as a result of radiation Mass spectrom- etry profiles of double-charged peptides eluted from corresponding rpHPLC fractions from nonirradiated and irradiated cells as indicated. The peptides marked by an asterisk are observed in both profiles, whereas the arrow indicates peptide
- A schematic view of radiotherapy-induced immune modulations. #1, tumor-associated antigens are released by irradiated dying cancer cells. TAAs and cell debris are engulfed in the tumor microenvironment by phagocytes such as macrophages, neutrophils, and dendritic cells for antigen processing and presentation. #2, radiotherapy-induced cell death releases danger signals, including HSP, HMGB1, and calreticulin (“eat-me” signal for phagocytes). #3, radiotherapy induces increased expression of tumor antigens and MHC class I molecules on tumor cells. #4, radiotherapy-induced T-cell activation increases expression of negative stimulatory molecules such as CTLA-4. #5, certain radiation doses may increase tumor production/secretion of immunosuppressive cytokines such as IL-10 and TGF-β. #6, activated APCs migrate to the draining lymph node, further mature upon encountering TH cells, release IFNs and IL-12/18 to stimulate TH1 responses that support the differentiation and proliferation of antigen-specific CTLs. Activated antigen-specific CTLs traffic systematically from the draining lymph node to infiltrate and lyse primary and distal tumors. RT, radiotherapy. DAMP are recognised by the innate immune system as danger signals. And function as an eat-me signal
- A schematic view of radiotherapy-induced immune modulations. #1, tumor-associated antigens are released by irradiated dying cancer cells. TAAs and cell debris are engulfed in the tumor microenvironment by phagocytes such as macrophages, neutrophils, and dendritic cells for antigen processing and presentation. #2, radiotherapy-induced cell death releases danger signals, including HSP, HMGB1, and calreticulin (“eat-me” signal for phagocytes). #3, radiotherapy induces increased expression of tumor antigens and MHC class I molecules on tumor cells. #4, radiotherapy-induced T-cell activation increases expression of negative stimulatory molecules such as CTLA-4. #5, certain radiation doses may increase tumor production/secretion of immunosuppressive cytokines such as IL-10 and TGF-β. #6, activated APCs migrate to the draining lymph node, further mature upon encountering TH cells, release IFNs and IL-12/18 to stimulate TH1 responses that support the differentiation and proliferation of antigen-specific CTLs. Activated antigen-specific CTLs traffic systematically from the draining lymph node to infiltrate and lyse primary and distal tumors. RT, radiotherapy.
- A schematic view of radiotherapy-induced immune modulations. #1, tumor-associated antigens are released by irradiated dying cancer cells. TAAs and cell debris are engulfed in the tumor microenvironment by phagocytes such as macrophages, neutrophils, and dendritic cells for antigen processing and presentation. #2, radiotherapy-induced cell death releases danger signals, including HSP, HMGB1, and calreticulin (“eat-me” signal for phagocytes). #3, radiotherapy induces increased expression of tumor antigens and MHC class I molecules on tumor cells. #4, radiotherapy-induced T-cell activation increases expression of negative stimulatory molecules such as CTLA-4. #5, certain radiation doses may increase tumor production/secretion of immunosuppressive cytokines such as IL-10 and TGF-β. #6, activated APCs migrate to the draining lymph node, further mature upon encountering TH cells, release IFNs and IL-12/18 to stimulate TH1 responses that support the differentiation and proliferation of antigen-specific CTLs. Activated antigen-specific CTLs traffic systematically from the draining lymph node to infiltrate and lyse primary and distal tumors. RT, radiotherapy.
- An another experiment has shown that in this regard , SBRT or hypofractionated doses works better compared to conventional fractionation. The diagram on top showing the number of APC within draining LN, and the diagram below showing the IFN production by TIL
- RT alone PDL1 up But in combination with Anti-PDL1 – more binding.
- anti-OX40 agonist anti- bodies, which act as T cell co-stimulatory agents, improve radiation efficacy when delivered shortly after radiation.
- optimal timing of anti-CTLA4 is before radiation mechanism of action of anti-CTLA4 has been associated with its ability to deplete regulatory T cells in the tumor
- TSA mouse breast carcinoma 9H10 is antiCTLA4 antibody Suggests cooperation between hypofrac RT and check point inhibition
- TSA murine breast carcinoma In terms of infield control 30Gy was similar 8 Gy x # However for abscopal response, 8 Gy x 3 fared much better (when combined with anti CTLA4 antibody) 8Gy x 3 regimen induced interferon beta, whereare single fraction 20Gy did not.
- RT driven anti-tumour imunity is related to the amount of cytosolic DNA that is produced. Cytosolic DNA activates the cGAS/STING pathway, which is involved with IFN production Based on the graph on the right, this seems to increase in a dose dependent manner until an inflection point where is reduced. This has been shown very nicely to be related to the Trex 1 activity. Which degrades cytosolic DNA. Based on this paper, it seems like TREX is ampliafied with higher fraction sizes
- It remains unknown whether irradiation of the DLN affects combinatorial efficacy with immune checkpoint block- ade (ICB). These studies show that ENI restrains the potent adaptive antitumor immunity that can be achieved by com- bining stereotactic tumor-directed radiotherapy and ICB. Mechanistically, ENI modulated chemokine signaling, leading to reduced immune infiltration as well as to an unfavorable balance between tumoricidal and immunosuppressive intra- tumoral immune cells (reflected in a decreased CD8 effector- to-Treg ratio). Exclusion of the DLN from the radiotherapy target volume should be examined in future clinical trials to promote synergy between ICB and radiotherapy.
- Not much data out there But definitely there is a growing interest This was an experiment on 4 cell lines. Amongst many things, they looked at whether calreticulin expression was increased comparing photons and protons. They showed that both increased calreticulin, but there was no increased expression with protons. What I am waiting for are on studies comparing photons to heavy ions.
- Resistance was common even with RT + Anti CTLA 4 - and this was shown to be due to PDL! Upregulation The addition of PDL1 bloackage reversed the T-cell exhaustion Pie charts show proportion on complete responses (in yellow) Secondly giving RT increased the diversity of the TCR receptor which goes back to the intial point that RT creates new peptides