Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘immune escape’

When the boat comes in

Much has been written about new and emerging immuno-oncology targets where we can add new targeted agents to existing immunotherapies – after all, quite a few have already tried and failed in clinical trials to shift the survival curve upwards and to the right.

Can it be done?

I firmly believe so, but this endeavour is going to take the whole field much time and energy, as well as quite a few iterations in molecule and trial design.  No one knows what the next big target is though, but when they do it will be a bit like when the boat comes in – you know it when you see it.

In the spotlight today is a relatively obscure target we have written about perhaps once or twice before and now there is suddenly burgeoning interest in this subniche with a couple of players already active in the space.  Will there be others? Maybe, it will likely depend on how the phase 1 trials pan out.

We have attempted to cover a couple of key questions:

  • What can we learn about the science and research conducted thus far?
  • Why is a big biotech company suddenly interested in this target?
  • Which tumour types look like being important?

Most importantly, though, a long time reader wrote in and asked why on earth is there sudden interest?  Will start a new stampede?  Who are the competition?

Good questions, and now we get to set the scene to explain what’s what and why the target matters…

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CAR T cell therapy for solid tumours is the cancer new product development equivalent of the quest for the “Holy Grail.” It remains one of the cell therapy challenges of the coming decade.

Light inspires and illuminates

In this post we shine the light on one of the world’s leading cell therapy experts who is taking on that challenge.

Most of our posts are what is known in the business as “long-form” and this one is no exception; it’s over 7,000 words long and offers a veritable smorgasbord of insights into new cell therapies for blood cancers and solid tumours, novel targets, as well as future directions, including a company in stealth mode…

Curious to learn more about this important topic on cracking the code and the quest to find solutions?

Then consider supporting independent science journalism by joining an exclusive group of readers around the world in academic medicine and industry who read BSB premium content.

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When should someone receive CAR T cell therapy? How do we identify who will benefit most or who will be most likely to fail? Those are some of the questions we’re considering in our latest expert interview.

As we see the landscapes around aggressive lymphomas and multiple multiple evolve and change with more near-term CAR T cell therapy approvals coming, so too do the clinical questions surrounding the optimising of these novel approaches.

Prof John Gribben, President of EHA (right) at CART2020 in Sitges

At the EHA/EBMT 2nd European meeting on CAR T cell therapy, BSB spoke with Professor John Gribben. He’s the current President of the European Hematology Association (EHA) and holds the Gordon Hamilton Fairley Chair of Medical Oncology at St. Bartholomew’s Hospital, Barts Cancer Institute, Queen Mary, University of London.

One of his messages was when considering CAR T cell therapy, it’s a delicate question of balance.

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In our latest expert interview, we depart from the usual focus on one of two particular or narrow topics and indulge in a more wide ranging discussion to explore a variety of issues facing the IO field and look at them from the perspective of a researcher who is experienced in working with antibodies in various forms.

We cover a lot of ground from CAR-T cells to bispecifics to NK cells – while many people in industry may see these approaches as separate modalities in different niches, in the future we may well see a greater convergent and opportunities for regimens and combinations rather than a more nihilistic either/or approach.

I have long been fascinated with design of molecules and how different tweaks or enhancements can change the way something works – for better or worse. Just as we have learned much from immune agonists and their biphasic curves that result from constant stimulation (and ways to fix that too), so too will we see CARs, T cell engagers, and NK cell therapies adapt and improve in terms of how they are constructed.

Who better to talk about these changes and the learnings to be had lately than someone who has built and tested many antibodies for a living and is now running his own company?

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DC sculpture

Up on deck today we have some highlights from my notes from SITC18 session on Immune Escape: Current Understanding of Mechanisms and Advances in Therapeutics Approaches held on November 7th, 2018.

This is a topic that I find particularly fascinating, not least because it has distinct parallels with what we have learned from chemotherapy and targeted therapies over the last couple of decades, so why not immunotherapy too?

Semantically, I’m not hung up on terminology either – call it resistance or immune escape, the negative effect on therapy is what matters and even some of the mechanisms are similar, such as the development of JAK mutations, for example.

The important point there was plenty to think about and consider in terms of what the data tell us from the patient tumour analyses and where they might direct us in terms of future research as well as novel combination approaches.

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Finding patterns in the mosaic of cancer biology

In our fifth AACR preview of the annual meeting of 2018, we switch directions from a tumour type to explore a novel and emerging pathway of interest.

Each year we pick a different target to explore; this year it’s the turn of TGFβ.

There’s a lot going on here, both preclinically and clinically that should interest BSB readers who are keen to see new developments in the IO landscape.

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Non-small cell lung cancer (NSCLC) is big news this morning with the announcement from Genentech/Roche that the IMpower150 trial exploring whether adding atezolizumab to the standard of care Avastin plus chemotherapy hit it’s first co-primary endpoint of PFS. The data will be presented at European Society for Medical Oncology (ESMO) Immuno Oncology Congress in Geneva, Switzerland next month. The other co-primary endpoint, overall survival, is expected in a couple of months.

I’m delighted that this trial hit a positive note, especially after a few folks were surprised at our emphatic positive prediction for both the PFS and OS outcomes in reviews this year when we looked at it in the summer and again in the fall – see: predictions in 1L NSCLC trials followed by red and green flags.

In the meantime, recently there was some very important news in the lung cancer niche relating to the field of genomics and our understanding of how tumours develop and evolve.

It’s easy for many folks to forget that even in a tumour type that is considered to be a hot/inflamed one due to the high tumour mutation burden (TMB), not all patients respond to checkpoint therapy upfront and not all will achieve lasting durable responses that go out five years. Resistance (primary and acquired), as well as immune escape, will inevitably have a large impact on many patients.

Understanding the underlying biology of the disease will not only help us figure out the causes of non-response and relapse, but also explore rational combination approaches that might improve outcomes.

Just as the triplet of atezo/bevacizumab/chemo has now been show to be superior to the control doublet, we may well see other approaches evolve in the near to medium term future.

The Dynamic Duo at #TARGETS17

Up on deck today is a timely yet rare joint interview that explores the science behind how cancers (including lung cancers) evolve and adapt to try and evade not only detection, but also being destroyed, by anti-cancer therapeutics.

Professor Charles Swanton (Crick and UCL) and Dr James Gulley (NCI) make for a thoughtful and compelling double act.

It was an absolute delight and a privilege to conduct our latest BSB fireside chat with them together. What they had to say was fascinating.

Often we have jested about putting researchers in the BSB hotseat, but frankly when it comes to people of this calibre, the tables are usually turned and the interviewer is the one in the hotseat with some selective pressure to keep up and maintain a flow of intelligent questions!

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SITC 2017

Treatment with checkpoint blockade has undoubtedly improved the lives of some people with advanced cancers such as melanoma and lung cancer, however the number who do achieve complete remission with single agent therapy is low (typically <20%).

In addition, not all people will respond up front while others achieve an objective response then relapse as acquired resistance or immune escape hits.

One challenge facing the field is identifying these mechanisms of resistance and finding the optimal combination approaches that lead to improved outcomes.

This weekend at the Society for Immunotherapy of Cancer (SITC) annual meeting, there were quite a few interesting new combination developments with early data.

Here, we take a look at one such combination to explore the data, the biomarker research that is ongoing and also some of the challenges associated with finding needles in the proverbial haystack…

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As we demonstrated in the recent Novel Targets podcast that opened Season 3, one topic that is a key focus for many in the IO space is addressing mechanisms of immune escape and acquired resistance to single agent treatment with immunotherapy.

We’ve seen several oncogenic escape mechanisms reported, included activation of the JAK/STAT pathways in some patients and loss of existing immunity when the tumour suddenly becomes cold or an immune dessert.

The good news is that there are a number of ideas that can be pursued, including activating the innate immune system in various combinations.

As we see more companies invest in the innate immunity space in order to have a rational partner with which to combine with their checkpoint inhibitor, it will be important to maintain focus on trial designs and synergistic mechanism of actions to improve efficacy while reducing the potential for overlapping or severe toxicities.

Here’s one intriguing and promising new approach that caught our eye this month that is worthy of researching and following over time…

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The majority of patients do not respond to cancer immunotherapy. That’s a fact. If you don’t have an immune response to start with, there’s no point giving a checkpoint inhibitor on its own because there are no T cells present in the tumor.

Dr Bernie Fox (@BernardAFox), a world leading cancer immunotherapy expert from Earle Chiles Research Institute in Portland, nailed this a year ago on the Novel Targets Podcast:

“What I teach the first year medical students is that if you have metastatic cancer, the only thing that makes a difference in your life is whether you’ve got your immune system turned on. If it’s not turned on, it doesn’t make a difference what you get, chemo, radiation, surgery, you aren’t going to do well.”

Lincoln Memorial, Washington DC

As we have seen with targeted therapies, drugs can also stop working as a result of acquired resistance. This is also true with cancer immunotherapy treatment.  Cancer constantly evolves and finds ways to bypass or evade detection or ways to kill it.

Faced with a complex jigsaw where we only have some of the pieces in place and an evil double sided version as a model for sneaky advanced cancers, where are we in overcoming cancer immunotherapy resistance?

At the recent AACR annual meeting we spoke with a rising star – an up and coming thought leader in the field of cancer immunotherapy who has taken all the disparate information out there and come up with a perspective on where the field is at and where it needs to go.

Jason Luke MD FACP (@jasonlukemd) is an Assistant Professor at the University of Chicago where, as a medical oncologist, he leads multiple early stage cancer immunotherapy drug development trials and treats patients with melanoma.

Dr Jason Luke AACR17

Working with colleagues such as Dr Tom Gajewski, he has a unique perspective on cancer immunotherapy resistance, and how to overcome this. Dr Luke kindly spoke to BSB in Washington DC.

This is the 3rd post in our series of expert interviews from AACR17.

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