Motivation
Immune therapies have radically changed the way Melanoma is treated and are now giving patients with advanced disease a real chance to survive.
Unfortunately, not every patient responds to treatment with single immune therapy so combinations are the hope.
This session will look at how to combine immune therapies with each other, with targeted therapies or with radiotherapy- so more options for patients.
Session, Friday 1st June 1pm
https://iplanner.asco.org/am2018/#/session/13123
Lex Eggermont on the new developments in Melanoma
Interesting to note- the interplay between targeted therapy and immune response, Lex quoting the paper by https://academic.oup.com/annonc/article/27/suppl_6/1111O/2799916# showing that complete responders on targeted therapies had tumours with signs of immune response.
Further to note-
Day 8 already T-cell infiltration and peaks at d15 under BRAFi +/- MEKi- this could mean one could use targeted agents to drive T-cell infiltration into tumours before starting on immune therapies
(will be presented on a poster this year)
Something to read up on - chemotherapy can induce a cell death that drives immune response
Michaud- 'immunogenic cell death' Science 2011
Zitvogel & Kroemer for review on which therapies can activate an immune response and which ones don't
Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents
https://www.cell.com/cancer-cell/abstract/S1535-6108(15)00389-XWhere things can go wrong in immune response and what to do
- CTL progrmming - CTL4 antibody
- CTL executive function - PDL1 antibody
- CTL tumour infliltration
- Immune escape mechanisms
DTIC leads not to immunogenic cell death, so combining Ipi with DTIC was not better than Ipi alone.
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NOTE
Combinations of Ipi plus have now been replaced by combinations of PD1 plus due to toxicity
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Lex' opinion
PD1 Monotherapy is already very successful, so showing that combinations are BETTER will be hard to demonstrate, especially in Melanoma.
So what can we do to explore combinations?
And yet again CheckMate 067- underpowered to answer the relevant question namely vs Ipi+Nivo was better than Nivo mono!
*we should not be running trials like this*
but it LOOKS as if difference between Ipi plus Nivo versus Nivo hardly better but with more toxicity
And NOW the interesting bits:
Salvage protocol:
Ipi low dose of 1 mg/kg plus Pembro directly given upon progression on PD1 leads to
47% response rates with a 12% complete response rate.
So that means that patients progressing on PD1 can receive the combo but we don't have to expose all patients to higher toxicity (FIND POSTER)
T-Vec plus Pembro
57% ORR irRC but not so good in visceral mets
So- the solution might not be combinations but rather smart sequential scheduling at the best point of time. Good finally they got that
The Elephant in the room-
Macrophages in the tumour create a very immune-suppressive
environment
Drugs targeting macrophages could be the next 'thing'
M2-M1 repolarisation lead to T-cell infiltration: CCR5, CXR2/ CXCR5
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The link between targeted therapies and immune response
Jennifer Ann Wargo
Targeted therapy leading to tumour infiltration of T-cells, so there is a rational to combine targeted therapy with checkpoint inhibition.
Cooper et all 2014 Cancer Immunol Res (Arlene Sharpe et all)
http://cancerimmunolres.aacrjournals.org/content/early/2014/04/29/2326-6066.CIR-13-0215
Interesting- pre-treatment immune signatures cannot predict whether a patient will respond to PD1 blockage.
BUT when you look after therapy started you do see a correlation.
Pei_Ling Chen Chancer Discovery 2016
Take home- biomarkers early on treatment might be better than biomarkers before the treatment starts
Microbiome
High diversity and the 'right type' in the gut biome correlated with better clinical results to checkpoint blockade
Gopalakrishnana et al Science 2018 -testing faecal transplantes in mice
Neoadjuvant treatment with targeted therapy
70% Melanoma patients progress after surgery alone- so there is a high motivation to use neo-adjuvant treatment
Published in
Amaria, Lancet Oncology 2018
READ
Had to close the trial because patients relapsed after surgery- while the ones who got neo-adjuvant and adjuvant therapy in addition to therapy didn't to the same degree.
In the question session- getting antibiotics right before or when you start PD1s correlates with worse response to anti-PD1s.
Neoadjuvant treatment with checkpoints
Ipi plus Nivo better than Nivo alone but high toxicity
International Neoadjuvant Melanoma Consortium now started
so hopefully advances will be fast.
http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.9581
Radiation and checkpoints
Marka R. Crittenden
- tumor antigen release
- tumour adjuvant release (DAMPS)
- Deletion of anergic T-cells
Abscopal immune response
Radiation can work like an endogenous vaccine- response in the tumours that have not been irradiated
antigen without adjuvant can lead to tolerance
adjuvant without antigen can lead to immune suppression
priming versus boosting an immune response- READ UP
Radiation-induced immunogenic modulation of tumour enhances antigen-processing
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964216/
- Single dose seemed more effective than split in smaller doses (hypofraction)
- timing between radiation and therapy matters- watch out about optimal window
- will depend on agents used
- fractionation might be good but might lead to lymphopenia
Young PLOSone 2016
Starting with Ipi then radiation better than parallel- READ UP
Immunogenic modulation- the radiation changes the tumour environment to let T-Cells work better
Wolchok NEJM 2017- 44% ORR of anti-PD1 plus radiation
Something to keep an eye on
High dose IL-2 plus radiation- 66% ORR in lung and liver mets
Seung
Important points
Radio promising BUT watch for dose, timing and fractionation.
Immunocompetence is important in local control following radiation.
Immunogenic modulation following focal radiation- only happens in the tumour.
Patient failed radiation, failed PD1 but adding single dose 8Gray let to response in the irradiated lesions- the patient was NED in the end.
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