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Going back to basics

We have written about a huge variety of different approaches to cancer research since 2006 but few are as intriguing as using pathogen-based approaches involving viruses or bacteria to stimulate or re-activate the immune system. After all, when such foreign bodies break through the physical barriers and enter the bloodstream, the immune system instantly springs into action to tackle them.

Can this knowledge be used effectively in the design of anti-cancer therapeutics?

We have seen some promising initial results with oncolytic viruses, but what about bacterial based approaches? Can a different approach to drug scaffolds yield improved results?

Here, we look through the window at a novel platform using immunotoxins in early development that may well pique a few people’s interest and offer our latest thought leader interview discussing the approach…

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Chipping away at cancer

As we follow the journey of various neoantigen and neoepitope approaches from start-up and preclinical research through to the clinic, it’s been interesting to see how different companies and academic research groups have chosen to consider their R&D strategies.

Some of the companies we’ve interviewed and highlighted in this space include Neon Therapeutics, BioNTech, Gritstone, and newcomer, Achilles Therapeutics, along with various academic programs such as George Coukos’s neoepitope vaccine approach in Lausanne.

After we first spoke with Gritstone a couple of years ago, things seemed to go a bit quiet on the western front while Neon, BioNTech, and Achilles all had news to talk about. It’s always hard to choose from rock-paper-scissors and this may well be another modern twist of that genre until clinical data proves otherwise.

That all changed with more data being presented by the California-based biotech recently, plus patients are also being enrolled into their first neoantigen clinical trial.

At a recent conference, we caught up with their CMO, Dr Raphael Rousseau, to find out more about where they are and importantly, where they’re headed…

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Incysus Targets GBM with Gamma Delta T Cells

If the best way to predict the future is to invent it then the poster sessions at the AACR annual meeting are frequently a window into the next generation of cancer drugs and therapies. Regular attendees at AACR will know that there are gems to be found in the posters, and that preclinical research on display may end up being translated into the clinic not long afterwards.

Like wearing a new set of clothes for lunch and dinner, with the exception of the first and last days, there’s a different set of posters in the morning and afternoon – that’s a lot of posters one can get through during a conference!

Indeed, MSKCC Chief Analytics Officer, Ari Caroline, noted on Twitter, “I may have spent more time at AACR this year at the posters than at the sessions.”

One story that we continue to follow this year is the emerging interest in unconventional T cells. The good news was that there was new data at AACR19.

We covered Puretech Health and their posters last week while another related one in the same niche that caught our attention was presented by Dr Lawrence Lamb (right).

On April 1, 2019 Incysus announced that the FDA had approved their IND application for a novel gamma-delta T cell therapy for treatment of patients with newly diagnosed glioblastoma (link to press release).

At AACR19 we met up with Dr Lamb, who is now Chief Scientific Officer of Incysus Therapeutics, to find out more about his research and how Incysus plan to translate it into the clinic.

This is a continuation of our series on gamma delta (𝞬𝝳) T cells exploring the multitude of different ways that illustrate their potential for cancer immunotherapy in hematologic malignancies and solid tumours.

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Going beyond BCMA as a target in multiple myeloma

With the startling news this morning that Poseida Therapeutics are abandoning their IPO plans and pursuing a different tack with a $142M investment from Novartis to fund clinical trials for their BCMA-directed CAR T cell therapy program in multiple myeloma, our attention is focused yet again on the highly competitive BCMA niche.

Poseida’s data was revealed at ASH last December and with an ORR of 63%, the initial efficacy was a bit lower than we have seen from rivals Bluebird Bio and Legend/JNJ, although the Penn/Novartis construct reported disappointingly lower responses in a small cohorts of patients, which may explain Novartis’s interest.

There are also other companies/products in this niche including GSK’s ADC, GSK2857916, and Amgen’s T cell bispecific, AMG 420, plus plenty of others with BCMAxCD3 bispecifics who have earlier skin in this increasingly highly competitive game.

Is BCMA enough though? Is it really the answer to multiple myeloma or are there other approaches that might be better?

Putting new CARs in the spotlight

What of the future for CAR T cell therapies in myeloma beyond the initial generation 2.0 constructs?

We saw a vision for how this market might evolve and sought out some experts to learn more about what they are doing in this niche – what they had to say was really interesting.

After all, as Wayne Gretsky would say, don’t skate to where the hockey puck is (now) but where it will be… that’s a great analogy one cannot resist borrowing for the future of cell therapy in multiple myeloma.

In our latest article, we go beyond BCMA to explore where we think the field might be going and why a tunnel focus on BCMA might not be such a great thing…

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Targeting the adenosine pathway in cancer immunotherapy

The AACR19 ‘mosh pit’ where gems abound

It’s been a while since we looked at the adenosine pathway, where a fog of immunosuppression is thought to cloak the ability of the immune system to induce antitumour immunity.

When we first wrote about the A2A receptor-CD73-CD39 pathway in 2016 there really weren’t very many players in this niche. Since then the field has expanded quite considerably and there are now more companies and molecules to consider.

As we straddle AACR and ASCO, it’s a great time to offer an update and look at what we learned…

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Are 𝞬𝝳 T cells immuno-suppressive and should we delete them?

We’re continuing our series following the development of novel cutting edge strategies targeting gamma delta (𝞬𝝳) T cells, with a look at the two approaches Puretech Health are pursuing based on the research of Dr George Miller (NYU Langone).

Data was presented at #AACR19 for a first-in-class immunotherapy targeting immune-suppressive delta 1 containing 𝞬𝝳 T cells and one targeting Galectin–9.

Drs Panchenko and Filipovic at their AACR19 poster

We recently spoke with Dr Aleksandra Filipovic, therapeutic lead for oncology at Puretech Health, she’s pictured right with Dr Tatyana Panchenko from NYU Langone at their AACR poster.

Dr Filiopovic told BSB that Puretech are looking for the next big IO breakthrough:

“We looked at this landscape and the massive amount of trials going on. We said ok, if we’re going to go into the space of immuno-oncology, what is it that we need to do differently in order to, upfront, try and ensure that we’re going after targets which could be the next PD–1. Our thinking went along the lines that we would really need to identify those next checkpoints, those next foundational modulators of the immune system.”

This is the first of two interviews from #AACR19 on novel strategies to target 𝞬𝝳 T cells, an emerging area that companies are looking at with both antibody and adoptive cellular therapy approaches. Do check out our previous mini-series if you missed it.

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Targeting neutrophils for 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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Going beyond PARP inhibitors to improve cancer outcomes

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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The Future of Cancer Immunotherapy Biomarkers

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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How confident can we be in the reproducibility of the IMpassion130 results in TNBC?

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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