Take- home messages from ASCO 2018

This wasn't an ASCO of big Melanoma news but rather of a series of important updates, insights and 'keep-in-mind's



My (Bettina's) take-homes are here 

Stage 3 and earlier

• Nivo better than Ipi adjuvant and no one should talk about Interferon in this context anymore 
• Complete Lymph Node Dissection comes with side effects but is not better than observation when it comes to overall survival
• tumour burden </> 1mm in the sentinel node is an important prognostic factor for Stage 3A although it's not part of the new AJCC 8th classification
• adjuvant for Stage 2 is coming- so watch out for trials

Stage 4

• there is something about Ipi contributing to the long-term effect of immune therapy we need to keep an eye on
• several combinations have potential to work after resistance to PD1
• checkpoint therapy can be stopped upon complete response or stable disease, many patients remain stable but re-challenge works upon progression
• brain mets remain a major problem, still nothing satisfying for leptomeningeal disease

General

• We consider Stage 1 T1a and b Melanoma as the 'lucky ones' who are cured by surgery alone. However, there is more to the story and looking at 20 year overall survival is sobering- a figure G. Long showed:

Ref- https://link.springer.com/article/10.1245%2Fs10434-017-6325-1

• The idea that Melanoma first goes to the local lymph node and then spreads further is done with- Melanoma can unfortunately spread both via lymph and blood straight from the beginning. 
• There remains a lot of work to do in terms of multi-disciplinary teams: we were in sessions where the surgeons wanted to operate, the radiologist to irradiate and the oncologist to drug. I'd like to see a long-term strategy that ensures that patients survive with as little side effects and long-term damage as possible.

Education is more than information- and what do we educate for?

This year at ASCO again and in several meetings we had, there was a lot of talk about patient education. And I begin to notice that some of it just sits uneasily with me.

Firstly I believe that there is a confusion between information and education. A leaflet or a website can provide information- but unless a patient has understood the content and can act on it, it isn't education. It's just- information sitting there.

And then- what do we educate for in the first place? An awful many demands for 'patient education' reek of self-interest. 

'Education' for patients to follow a physician's instructions seems a contradiction in itself- you either demand uncritical obedience, that's an order but not education. Or you educate patients about the reasons why a physician makes certain demands. In that case, the educated patient might well disagree with a physician's judgement and act otherwise. There is maybe manipulation into obedience but education always offers more and not fewer options.

Then there is 'education' for patients to donate money, their time, their blood, their tissue samples and sometimes their lives- you just have to remember the series of equipoise-violating Melanoma trials we have had. 
These are valuable resources, so surely true education would provide patients with the knowledge to choose when, where and to whom to provide their support. 'For scientific progress' or 'the greater good of humanity' rather sounds like a poor sales pitch in this context, especially considering the normal distribution also replies to research- the good, the bad and the ugly are alive and kicking also here.

In my mind, you cannot 'educate to do', only 'educate to empower'- give patients and people in general the information and understanding to make informed decisions on their own behalf. One might sometimes agree, sometimes not. 
Patient education should provide knowledge and more options and with that, a higher degree of protection.

Options for those progressing on anti-PD1 - Early Clinical Trials and Reports

Here  - early agents in combinations, some promising for those progressing on anti-PD1 monotherapy!

Abstract 9514
Treatment after progression on monotherapy with anti PD1 (pembro)
Adding ipilimumab:
Complete Response rate (CR) 13%
Overal Response Rate (ORR) 45%

Abstract 9515
Tilsotolimod (TLR9 agonist) + IPI in patients progressing on anti-PD1 monotherapy
21 pts
Disease Control Rate -71%
Overall Response Rate 38.1%

Abstract 9513
SD-101 is a TLR9 agonist administered by local injection
By targeting TLR9, SD-101 helps dendritic cells to convert in APCs (Antigen Presentation Cells) and stimulates the anti-tumor activity of T-cells.

Trial SD-101 + Pembrolizumab
54 patients treated with SD-101 in an 8-mg dose in one lesion and 2-mg dose per lesion for two to four lesions beginning 21 days following the first dose pembrolizumab dose.

Efficacy
PFS 6 months -76%
ORR- 70% in naive patients (no previous treatment)
ORR -15 % in patients previously treated with an anti-PD1

Staging- particularly important for Stage 3 patients

Recent update from AJCC 7th to 8th edition


Stage 3 has now 4 substages


Study- externally validate new edition for prognosis and help with decision-making


Main take home- Stage 3D describes a patient group at very high risk

SN Tumour Burden 

cut-off of 1mm strongly correlated with survival- 


Stage 3A can be further stratified by Sentinel tumour burden 

< 1mm  91% 5 year OS
> 1mm  72%   5 year OS

Verver et al Eur J Cancer 2018

Hope that it will help avoid Complete Lymph Node Dissections in the future.



DECOG- SLT update-

CLND vs observation in patients with a positive Sentinel Lymph Node


Overall survival and Recurrence-free survival= no difference

MSLT II (publised NEJM 2017) confirmed findings

Now median follow-up 72 months- 24.5% died 

point to follow up- where does metastasis occur- pic

difference between < or > 1mm in SLN but still, no difference between observation and CLND

and original tumour thickness  most relevant factors for OS

The power was powered to detect a differences of 10% in the DMFS to date the difference is 2.7% in favour of observation.


Halstedian hypothesis (1907)
Stepwise metastasis

Data supports parallel metastasis, not step-wise fashion.

Therefore- they no longer recommend CLND in micro-metastasis


According to Lex Eggermont- 95% of patients staged correctly by tumor thickness and sentinel lymph node burden, so only 5% would benefit from a CLND for better staging


Weber 

Checkpoint 238: 24months follow-up

Most recurrences in Stage 3 occur within the first 3 years (slide for refs)

Ipi adjuvant- RFS plateaus at 3 years


Checkpoint 238 - pointless blinding yet again

Nivo 3mg/kg vs Ipi 10mg/kg

• post-surgery
• no uveal, but acral and mucosal allowed

Primary endpoint: RFS, new primary Melanoma or death


Results

24th months 63 vs 50%

18th 66% vs 53%

12 months 70 vs 60%


Important take-home 

• PDL-1> 5% do better than PDL-1<5% but the difference between Ipi vs Nivo remains in favour of Nivo
• again- 3 C (AJCC 7th) do worse than 3B
• no influence of BRAF status

Very valid question- how far is the rate of screening failure?

20% screening failure- as it takes 28 days to include in trial, some patients had metastasis 4 weeks later, so were staged incorrectly at beginning

Summary of orals

1. Recommendation Observation not CLDN should be the standard after positive SLND (Germany has US follow-up every 3 months)

caution

- head/ neck excluded from study

- patients who don't follow tight follow-up at risk

2. Adjuvant treatments

for BRAF neg: PD1 adjuvant more effective and less toxic than Ipi

for BRAF pos: targeted therapy remains an option

3. New staging

There is a group of patients at very high risk (Stage 3D)- but is there also a group that might be spared systemic therapy? 

The big question- IIIA: treat now or later?

Wolchok NEJM 2017- 58% at 3 years OS

Recommendation

for patients with Stage 3B and above

For Stage 3A- adjuvant should be discussed and offered, in particular with tumour burden > 1mm.

• Best adjuvant for BRAF pos remains to be seen
• Neo-adjuvant vs adjuvant 
• Treatment of even earlier stage disease needs to be investigated

To note- Stage 3 not always tested for BRAF

fertility and endocrinopathies to be considered with immune therapies, in particular in young patients


The big question- can we stop Pembro?

4- ys OS after 2 yrs of Pembro KEYNOTE 006
Georgina Long


all patients were treatment-naive for Ipi, PD1, PDL1 but could have had targeted therapy. Patients with elevated LDH or tumour-related symptoms had to have targeted first

2 yrs of Pembro and 2nd dose of Pembro was permitted upon progression


3 yr 41.7% on Pembr 34.1% Ipi

Interesting to note that the duration of response was similar between Pembro and Ipi 

86% patients are progression-free after 20 months after completing 2 years of pembro

re-challenge is possible and works
slide



Columbus trial

Dummer

Enco - very long on target dissociation time- leads to sustained target inhibition


And yet another ugly bridesmaid design 1:1:1 
considering we know BRAF+ MEK is better than BRAF alone, so the combo can only look better than mono 

Enco 450 mg/ Bini  45mg vs Vem vs Enco 300mg

Immunotherapy biomarkers- beyond PDL1

PD-L1- Prognostic and Predictive State of the Science
Charles G. Drake

-normally is a negative prognostic biomarker in cancers
-as a predictor to the treatment response in melanoma -if you have a PDL1 the treatment could work

-in bladder cancer -PDL1 expression correlates with response to atezolizumab;
- unfortunately, within same cancer, same treatment we get different responses for the 1st line and second line, so different conditions could impact the ability of PDL1 to be a right predictor


Limit Utility
1) spatial Heterogeneity
2) which cells type to quantify
3) competing assay and metrics

In lung cancer is clinically used and recently was announced as a predictor in the blade cancer.
Translational research- in mouse models conflicting results.
Message-  still we cannot rely on it as a single biomarker, so in melanoma PDL1 cannot guide the treatment decision.


Tumour Mutational Burden (TMB)
Timothy An-thy Chan 
Memorial Sloan Hospital

TMB promising as biomarker to identify those people responding to immunotherapy; as seen bellow still we have a consistent percentage of non responders- unmet medical need

Human T-Cells - two important features to remember:
Tumour is part as non-self for our body (that is helping T-cells to recognize the tumor and attack it)
Immune system has memory, so what was recognize as enemy first time could be identified the second time too.
Having antigens and neo-antigens within tumors is helping the immune system to recognize the tumors as non self.

Multiple cancers benefiting: melanoma, urothelial, lung,, renal etc but we still have negative trials, so..what are the genetic determinants of benefit from immunotherapy (anti CTL4 and anti PD1)?
- mutation and neoantigen burden predict response in lung cancer to anti-PD1
- in melanoma- mutational burden a good indicator of response to ipi (for example)
- melanoma is highly immunogenic - got a number of modified proteins as a consequence of DNA damage (environmental factors)

High TMB (Tumor Mutational Burden)  and low TMB - in Checkmate 038, Keynote 012, 028 (solid tumors) (to be checked)
So- Hypermutated tumors - respond to anti-PD1
Clonal neoantigens - predict a better response
Patients with HLA +high TMB - do better on immuno
but how to integrate different biomarkers is the challenge in the future

Future Directions in Immunotherapy Biomarkers

Kurt Schalper

Challenges in developing biomarkers
foto
rules of cell functionality don't apply for the tumor cell
measure the metrics of T-cells

Tumors tissue biomarkers
CD3, CD8
Low TIL infiltrations
Patients with dormant TIL - DO the best
Active TILs did not so good on immuno (see foto)
By different techniques - we understand the imune compositions -effector  memory T cells, T cells activation, candidate targets etc.

Liquid biopsy
foto
TMB could be measured in blood too!
More in 2 abstracts (foto)

Serum IL-level in melanoma
BMS company validate this biomarker
low levels low responses and OS

Circulating immune cells and the response to blockers- good metric in patients with melanoma (foto)
Mieloid Derived Suppressors Cells - could be also measured -predict outcomes in certain cancers.

Integration and implementation in clinical practice - remains a challenge
No one could study alone the multitudes of biomarkers- so collaboration between labs is essential.

Questions:
1)Microbiome -promising but the mechanisms are not yet understood
and How we can we use that clinically?

2)PDL1 and TMB - they are independent predictors, what is the best?
-not yet convincing data what is the better- must be judged in context (first line, second line); and is not actually important what is better because they could be used together

3) Imaging - as biomarkers

4)TMB - could be different but responses to therapies could be sometimes similar -that means that there are also other factors involved (such as tumor microenvironment -hostile conditions for T-cells infiltration).

5)calculating TMB from liquid biopsy -how accurate is?

Related literature - Manson et al., 2016

A new hope: NKTR-214 plus Nivolumab

Preliminary data of PIVOT study were presented (see also Abstract 3006)
28 patients treated with the combination NKTR 214 +Nivolumab

Is known that patients with low baseline CD8+ T-cells (TILs) within the tumor microenvironment have a poor response to immune checkpoint inhibitors as pembro or nivo.  


So NKTR 214 is designed to activate and expand CD8+ T cells and improve clinical outcomes in patients with low TILs
-agonist =stimulates; antagonist= inhibits  

-NKTR-214 binds to CD122 receptors found on the surface of immune cells like CD8+ T cells and NK cells

SITC 2017- first data presented
SITC 2018 - second data


Patients were naive (no previous immunotherapy), both Braf positive and Braf wild (without mutation), with tumors expressing high and low PDL1.

Best ORR (overall response rate)
PDL (+) 62% patients
PDL1 (-) 42% patients
Unknown 33%

Remarkably after being treated with NKTR-214 +nivolumab  the tumors of more than 50% of patients with low PDL1 expression got a higher PDL1 expression. Patients having a high PDL1 expression at the start of treatment and patient whose tumors were converted to high PDL1 (+) were the ones with the most clinical benefit.

and ..conclusions!

Definitely, something to keep an eye on as this could transform non-responders in responders!

Brain mets in Melanoma

Motivation

Important topic as brain mets remain one of the biggest challenges in Melanoma.

Isolated progression in the brain while stable disease outside the brain.


Grant McArthur

Incidence and prognosis of Melanoma brain mets

• Melanoma is Number 3 reason for brain mets (after lung and breast cancers)
• Melanoma has the highest level of cerebral tropism (Wen 2012)- means it likes to metastasize to the brain
• 40-50% patients with metastatic Melanoma will develop brain mets
• brain metastasis huge impact on survival

Biology of brain mets

The brain is a special organ. 


NOTE
Metastasis from metastasis occurs 

Melanoma has the highest level of CD3, CD8 and PD1 positive T-cells in brain mets of all cancers = could explain why checkpoints also work in brain mets in Melanoma


Adler 2017- it seems that BRAFpos patients more likely to develop brain mets than BRAF Wt

https://www.ncbi.nlm.nih.gov/pubmed/28787433

Neo-angenesis (new blood vessels forming) promotes growth of brain mets- means blocking it could help controlling brain mets


Surveillance of brain mets in Melanoma

Lewin- 2018

5/ 43 patients with Stage 3C (with follow-up for 47 months) recurred with brain mets, 3 also had mets elsewhere but 2 were asymptomatic.

So challenge is to argue for tight MRIs as many will not progress but for those who progress in particular in the brain, this is dangerous.



Caroline Robert

Combinations of local and systemic treatments to treat brain mets

BRAFi works in the brain but less well than outside the brain
BRAFi plus MEKi- Davies 2017
Ipi- Margolin 2011- response in brain similar to outside the brain
Pembro- Goldberg 2017- also works in brain
Nivo plus Ipi- Tawbi ASCO2017- 55% response rate in brain
also Long 2018- Lancet

CR- what is missing are trials how to combine systemic and SRT- AGREE

Parallel systemic immuno therapy and radiotherapy did not seem to increase the risk of necrosis but timing essential as both radiotherapy and immune therapy can induce inflammation in the brain.

Bottom line is that the treatment of brain mets is evolving very fast, there is a lot that can be done, so it's not the time to just give up.


Hussein Tawbi, MD Andersson

First-line treatment of brain mets


Timing if IO and SRS critical
synergy only if both at same time or very close to each other.

Adjuvant/ neoadjuvant treatment in Melanoma

Neoadjuvant treatment

work in progress please keep coming back


Neoadjuvant = treat, then operate 
Intention: shrink tumour (to make surgery easier or possible) 


Ideal properties of a neoadjuvant treatment would be

• High response rate with predictable kinetics of response (so you know when to expect to see a result)
• tolerability
• Ease of use
• low cost (interesting to see this here right up front on the list)

Quick reminder-

In Stage 3, 5 year OS (overall survival) differs between 93% (IIIA) to 32% (IIID), so treatment options are needed. 

Theoretical Benefits of neoadjuvant

-improve/ allow surgical resection

- treat occult (hidden) metastasis earlier in disease

- assess whether disease responds to treatment

And it MAY

- treatment with immune therapies when tumour antigens are present MAY improve efficacy while reducing toxicity

- it MAY reduce surgery-induced immune-suppression 

Theoretical problems of neoadjuvant therapy

- if treatment doesn't work, progression might make tumour inoperable

- surgery can become more difficult because of local reaction

- patients might drop out (mhm considering that dissection on OS-benefit not convinced about that one)

- can affect later treatment options upon progression (e.g. to participate in a clinical trial)

- toxicity

BRAF/ MEK inhibitors

NOTE- recent Ph3 neo-adjuvant trial was stopped for efficacy of the experimental arm. 

Amaria 2018 (Lancet) 

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30015-9/fulltext

Checkpoints neo-adjuvant

Ipi- relatively low response rate with relatively high toxicity

PD1- response rate ok, low toxicity

Ipi plus Nivo- high response rate, high toxicity

T-Vec

• response rate 26- 33%, seems higher in transit mets than in nodal disease
• Grade 3/4 toxicity - 2% 
• not that easy to handle and patient has to come back every 2 weeks

Isolated limb infusion/ perfusion

high response rate 50- 80%
hospital admission, toxicity moderate (mhmm)
Considered for localised disease as treatment confined to affected limb



Georgina Long

Rationale of adjuvant vs neoadjuvant therapy

Lo, S Annals Surg Onc 2018
Stage 1 Melanoma OS

shows 20 year OS in even early stage Melanoma drops- READ


Neoadjuvant

single dose of PD1 neoadjuvant, than surgery
patients who achieve a complete pathological response do not tend to recurr


Adjuvant vs neoadjuvant
Rozeman ESMO2017
Differences in T-Cells mounting response between neoadjuvant vs adjuvant- more diversity when treating neoadjuvant

and again
PDL1 should NOT be used to direct anti-PD1 treatment- data to come on Monday


Best slide of this morning :-)

Sequencing therapies for Stage 4 Melanoma

Interesting session on how to use systemic therapies, radiotherapies and surgery in advanced Melanoma. 
Take home message however- there is *a lot* of personal judgement in there, so our take-home message would be- make sure you have a multi-disciplinary Tumour board and otherwise, get opinions from different specialities. 
In many cases, there is more than one possible approach and every single one comes with certain benefits and certain risks- and it's not at least up to the patient to decide what is acceptable and what not.

An interesting piece of information on LDH, CD8 T cell infiltration and PDL1 expression (all prognostic/ predictive markers): 

Novel Combination therapies in Melanoma

Paolo Ascierto


Progress in Melanoma has been enormous

Review on the therapeutic progresses made in Melanoma
https://www.ncbi.nlm.nih.gov/pubmed/28756137

but we still loose too many patients, so further options are needed and combinations likely to provide additional benefit.



READ

Elements of cancer immunity and the cancer-immune set point. 

https://www.ncbi.nlm.nih.gov/pubmed/28102259

Interesting question- is there still a role for IDO inhibitors? Remember the trial with Epacadostat and Pembro failed recently- now it remains to understand why the Ph2 looked promising but the Ph3 failed.


Possible combinations

LAG3 with PD1s

efficacy in combination with PD1 in patients who failed PD1

Big question now- why now a first-line trial?!


Other options- 

Entinostat (HDACi) plus pembro for patients who progressed on PD1

Johnson ASCO2017 poster

check also out- Hamm AACR 2018


CD122 agonist with PD1

NKTR-214 - Diab et al


Read up - how to target metabolism
Morella 2017

CD73 
AZAR
CD73 and A2AR inhibition
https://www.cell.com/cancer-cell/pdfExtended/S1535-6108(16)30388-9



Novel targets in Melanoma therapy
Keith Flaherty

BRAF, NRAS, NF1 and triple-WT Melanoma
(remember- absence of a marker does not suggest homogeneity)

CDKN2A biological important node in Melanoma


Remember
MEKi in NRAS mutant does not work as well as BRAFi + MEKi in BRAF mutant Melanoma

MITF low, Axl high predicts lack of response to BRAFi, unfortunately also the 'immunologically cold' tumours, so also not likely to correspond to immune therapy

Tirosh Science 2016

BUT high transcriptional heterogeneity within a tumour



Yuan PNAS 2013

Phenformin to target the metabolic state of persisting cells to add it to BRAF/MEK combination to prevent resistance 

Now tested in a clinical trial
https://clinicaltrials.gov/ct2/show/NCT03026517


Zhang JCI 2017 HSP


TILs


can work in patients who progressed on Ipi, PD1s and combinations

Schachter 2017 Lancet

Stage 3 Melanoma- surgery and adjuvant therapies

Practice-Changing Developments in Stage III Melanoma: Surgery, Adjuvant Targeted Therapy, and Immunotherapy

Sat, Jun 02 • 1:15 PM - 2:30 PM

 

Location: S406

work in progress please keep coming back

Alexander Van Akkooi- how much surgery in Stage 3?

A bit of history- Gould 1960 described the principle of the sentinel node that he saw when operating in the parotis (one of the glands producing saliva)- a lymph node draining lymph from a certain area. 

Now what is a Sentinel Node?

Definition

1st draining lymph node from the primary location (of the Melanoma for us)

Concept- a sentinel node as

A Incubator = assuming that progression follows a 'proper' order, going to the loco-regional lymph node first, then spreading further later

B Indicator = simultaneous hematogenic spread

prognostic information: node effected = worse prognosis

Read- Morton 2014

Lancet 2016- no benefit of complete lymph node dissection DECOG-SLT

MSLT-II: CLND vs observation and the Key result.....observation as good as surgery

picture

Grob et al 2018 on how staging shifts from AJCC version 7 to 8

https://www.skincancer.org/publications/the-melanoma-letter/2018-vol-36-no-1/ajcc-staging-system

Interesting to follow up on: neo-adjuvant immune therapy 

Summary

Sentinel node biopsy best diagnostic test

SN tumour burden is prognostic but has no certain therapeutical effect

CLND does not improve survival

For palpable nodes- neo-adjuvant therapy might reduce the extent of surgery necessary and help choose the right adjuvant treatment

Debate- targeted or immuno adjuvant for BRAF positive Stage 3 patients

Arguments for Adjuvant targeted therapy

Known facts

• Dab/ Tram improves OS in Patients with resected STage 3 patients
• improves RFS in same patients
• rare permanent toxicities

Targeted therapy adjuvant challenges known dogmas (only immuno provides long-term results)

Durability of response with targeted therapy in Stage 4, especially for patients with normal LDH and fewer than 3 organ sites involved

Overal argument to use targeted therapy adjuvant- Stage 3 patients have normal LDH and low volume micro metastatic disease

Read up

Long 2018

Schadendorf 2017 (CombiV-CombiD)

Overview

BUT

- higher rate of secondary skin cancers including secondary Melanomas- approx 2.3%

- testing BRAF in very low volume disease can be challenging

- 41% experience Grade 3 or 4 toxicity is high- but most all toxicity is fully reversible with drug discontinuation

Adjuvant immune therapy

Olivier Michielin

Immune therapy- metastatic vs adjuvant setting

Several options available, show DFS benefit but OS data still outstanding
Side effects are a challenge: toxicity on targeted is high but resolves when treatment stops while on immune therapy require experienced medical teams and might not resolve

Future- personalised adjuvant treatment

no treatment for those cured by surgery alone
e.g. stratification by whether patients are able to mount a diversity of T-cell clones against the tumour or not

Summary

- therapies in Stage 3 are rapidly evolving, we got first indications what works and what doesn't but we don't have the 'best way how to do it' yet

- Complete Lymph Node Dissection for all is no longer the way to go

- toxicity is a serious concern, especially as we are currently treating patients who might already be cured by surgery alone

- Stratification: who patient needs what will be the next challenge

RISK OF EQUIPOISE-VIOLATION
Placebos in Stage 3 trials are no longer ethical as we have data that shows that some therapies that delay progression and some data that shows improved overall survival

Immune therapies in combination

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-X


Where 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.


----------------------

NOTE
Combinations of Ipi plus have now been replaced by combinations of PD1 plus due to toxicity

----------------------

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




-----------------------------------------------------------------


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.