Biotech Strategy Blog

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

If we want to help more patients respond to initial immune checkpoint blockade then we not only need to figure out why some people respond initially but stop responding, but also look at why the majority do not respond upfront.

The reasons might take on many forms depending on the defects in their immune system that the cancer might have hijacked to its advantage.

One obvious way is increased immunosuppression and a more hostile tumour microenvironment. In the past, we have looked at the adenosine fog, as well as the cytokine, TGF-beta, as two quite different ways where the tumours might be impacted in terms of their responsiveness to therapeutic intervention.

In our latest mini-series this week, we are going to explore additional ways that cause non-response to cancer immunotherapy due to immunosuppression and how companies – big and small – are investigating novel therapeutic approaches in this niche based on the underlying biology of the disease.

We begin our journey with a look at neutrophils from the eyes of a researcher who is an expert in this field and how an understanding of the science has led to new novel targets with even some early stage compounds in the clinic already…

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DNA Damage Repair (DDR) has come a long way over the last decade or so from preclinical development through clinical trials, including some notable failures along the way. What began initially with PARP inhibitors, has now expanded into other related targets in the pathway, including ATM/ATR, WEE–1, Chk1/2, DNA-PK, and even Fanconi anemia genes such as FANCA/BC/D1, BRIP1 and PALB2, which are considered an indication of BRCAness where there is also chromosomal instability and homologous recombination.

Top 10 DDR targets and molecules at AACR19

At AACR last week, there was plenty to learn about in the ever-expanding DDR niche in terms of new data from a relatively new target such as DNA-PK to updated clinical data on WEE–1 and Chk1 inhibition to early data on PARP in a new tumour type to add to the growing list of ovarian, breast, and prostate cancers that are impacted by DDR therapies.

Included in this post are 10 key targets or molecules in the DDR niche that are of potential interest to readers – we explain why we included them and why the data matters.

Here we take a look at the highlights that we came across in this mini review, which should be useful preparation ahead of yet more clinical data likely being presented at ASCO and ESMO later this year.

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Continuing our in-depth oncology pathology interview with Dr David Rimm (Yale), we take a look at some of the new data his lab presented in Atlanta, where we are now with TMB as a biomarker, and what the future may hold for cancer immunotherapy biomarkers.

Early morning in Atlanta en route to the GWCC and AACR19

In an engaging discussion, Dr Rimm discussed many of the details behind PD-L1 and TMB in terms of what really matters when thinking about these tests and their practical applications. He also shared his candid thoughts on the lung cancer blood TMB data presented at AACR by Prof Solange Peters.

If you missed the first part of the interview with Dr David Rimm, a leading oncology pathologist at Yale, on the various challenges associated with PD-L1 as a biomarker on tumour and immune cells in triple negative breast cancer than you can catch up and read it here.

The second half of the interview with Dr Rimm focuses on TMB, with some more details on the challenges of reading PD-L1 on immune cells and why that is the case…

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One of the emerging challenges of the IMpassion130 trial of the combination of nab-paclitaxel and atezolizumab versus nab-paclitaxel alone in triple negative breast cancer (TNBC) is that pathologists can’t reliably read PD-L1 on immune cells.

Georgia State Capitol in Atlanta

This issue came up in an insightful talk by David Rimm MD PhD (@RimmPathology), Professor, Departments of Pathology and Medicine (Oncology) at Yale in an education session at this year’s AACR annual meeting in Atlanta where he spoke about, “Predicting immunotherapy response with protein-based tools: PD-L1 and beyond.”

BSB readers will recall Dr Rimm was a hard hitting discussant of the CheckMate–227 trial data for the combination of nivolumab and ipilimumab in first-line non-small cell lung cancer (NSCLC) at AACR18. He correctly predicted that tumor mutational burden (TMB) as a biomarker would predict PFS but not overall survival, based on an analysis of their cohort at Yale. He turned out to be right!

The implication of this was that BMS subsequently withdrew their EU/US regulatory filings for CM227 in 1L NSCLC when the hazard ratios (HR) for high and low TMB turned out to be identical.

If you missed it, do listen to the episode 22 of the Novel Targets Podcast we produced from AACR18 (Link), where we took a closer look at TMB as a biomarker, and the phase 3 lung cancer clinical data presented at the meeting.

Will we see challenges emerge with the Ventana SP142 assay?  What about the implications for Merck’s KEYNOTE-355 trial in TNBC?

In this BSB post, we discuss these issues and explore many of the nuances that readers should be aware of in TNBC.

In addition to Dr Rimm’s candid and hard hitting interview, we also invited Professor Sherene Loi (@LoiSher) to review Dr Rimm’s commentary and offer a clinical perspective on the points he raised.

She’s a consultant medical oncologist at the Peter MacCullum Centre in Australia, where she holds the National Breast Cancer Foundation of Australia Endowed Chair and is head of the Translational Breast Cancer Genomics and Therapeutic Laboratory.

Professor Loi is also one of the authors of the paper published in The New England Journal of Medicine that reported the results of the IMPassion130 trial.

If you’d like to read Dr Rimm’s candid interview and Professor Loi’s clinical perspective, become a subscriber to BSB and support independent science journalism. As of today, 75% of our subscribers are repeat buyers – do consider joining them!

In the second part of the interview with Dr Rimm (to be published separately), we’ll hear about some of the new data his lab presented at AACR19 and where he sees the future for TMB and other immune biomarkers.

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Atlanta – what’s exactly behind a poster board mobbing at AACR?

AACR19 Poster Hall

Is there some science or rationale behing the attention or is it something quite quirky and unexpected?

That was the critical question we wondered about as we traversed the poster hall sessions over the last few days and noticed the certain posters received more attention than others:

  • Why was this?
  • Is there a rhyme and reason to it?
  • Which ones were actually mobbed?
  • Is the attention justified?

If you’re curious like we were, then this is the post for you.

We highlight several posters from the AACR19 conference that received a noticeable amount of traffic and in future posts we will highlight those we consider to be gems from the poster halls and explain why, which… wasn’t necessarily quite the same thing (as being mobbed).

So without much ado, which ones were in the spotlight by AACR attendees this year?

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Packed sessions at AACR19

Atlanta – We’ve had a few requests to discuss the Apexigen anti-CD40 data presented by Dr Robert Vonderheide (Penn) presented at AACR19 on Sunday.

That’s a request we happy to oblige.

There seems to be quite a difference in reactions between researchers and investors on this issue, so it’s a nice opportunity to put the data in appropriate context.

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Atlanta: There is no shortage of innovative and potentially ground-breaking science on display at the annual meeting of the American Association for Cancer Research (AACR) that’s currently taking place in Atlanta.

AACR19 Poster Hall melee yesterday afternoon

What is noticeable this year is the large number of scheduling conflicts, i.e. interesting sessions or symposia all going on in parallel and that’s not including the poster sessions, where much of the early work is presented – you could spend much of the meeting in the poster hall alone!

It’s impossible for any outlet to do the meeting justice, so our selection of topics is subjective in nature.

We’ll be posting interviews and more in-depth pieces later, but in this post we take a look at what stood out for us in the Friday/Saturday education sessions we attended and in Sunday oral symposia.

As Frank Sinatra famously sang, “The best is yet to come,” with a tsunami of presentations and posters slated to be heard over the next few days.

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Pierre de Coubertin Statue, Atlanta

On BSB we write about the science driving innovation in the biotechnology and pharmaceutical industry, and how that translates into new product development.

One of our favorite meetings of the cancer conference calendar is the annual meeting of the American Association for Cancer Research (AACR). The 2019 annual meeting starts in Atlanta later this week and is the cancer research mecca that we and others will be heading to later this week.

Ahead of the meeting we’re continuing our #AACR19 previews with a look at some of the innovative, novel cancer agents we expect to hear more about in Atlanta.

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Centennial Olympic Park, Atlanta

In the first part of our preview we looked at the cancer immunotherapy related program from Friday through Sunday at the AACR 2019 (#AACR19) annual meeting at the Georgia World Congress Center (GWCC) in Atlanta.

This post looks at the program from Monday to Wednesday – you can find a review of the IO track for Fri-Sat here.

Don’t forget you can review the precise room details via the AACR meeting app prior to attending sessions as these are sometimes subject to change. We’ve based our posts on the preliminary program and it is highly likely there will be changes to meeting rooms, based on past experience.

If you’d like to read more about our current conference preview on cancer immunotherapy, subscribers can log-in to read our latest review of what’s going on or you can click to gain access to BSB Premium Content.

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We’re starting our review of the program for the forthcoming 2019 annual meeting of the American Association for Cancer Research (Twitter hashtag to follow: #AACR19) with a look at the cancer immunotherapy program.

One of the challenges of a large meeting is that it’s like a smorgasbord or buffet in a hotel that’s resplendent in choices, but you can’t possibly eat it all.

Choices!

Some choose to follow a research area, others a target or tumor type. There’s a lot of ways to segment the program depending on your specific interests.

However, it’s a good idea to have a plan in place ahead of a large conference such as AACR, even if you modify it as you go to take into account evolving needs.

Seasoned conference goers will be familiar with the maxim known as “the law of two feet” – if a session you are in doesn’t live up to expectations or meet your needs and something else looks more to your taste from the tweets, then simply dash off to another!

In our latest conference preview, we’ve taken a careful look at the cancer immunotherapy track.

What are some of the key sessions to put on your calendar if you’re following this track or have an interest in this area?

In Part 1, we review the IO sessions from Friday to Sunday then tomorrow in Part 2, we’ll review the schedule from Monday to Wednesday.  Yes, it’s that intense this year! Just think, five years ago you had to search the program really quite hard indeed to even find much on immuno-oncology, as it was very much in its infancy then.

If you’d like to read more about our latest cancer conference preview, subscribers can log-in to read our latest thought leader interview or you can click to gain access to BSB Premium Content.

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