Biotech Strategy Blog

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

Posts from the ‘Translational Medicine’ category

Dr Holbrook Kohrt StanfordHolbrook Kohrt MD PhD (pictured right) is a Stanford medical oncologist and clinical researcher who is leading the way in cancer immunotherapy combination strategies targeting CD137 (4-1BB).

He’s a speaker I greatly enjoy listening to at meetings. Earlier this year at The American Association of Immunologists (AAI) annual meeting (Immunology 2015) in New Orleans, he gave a noteworthy presentation on combination monoclonal antibody therapy.

The potential of a combination of an anti-CD137 monoclonal antibody such as urelumab plus an anti-CD20 such as rituximab, was one that he appeared to be particularly excited about.

Dr Kohrt kindly spoke with BSB and shared his thoughts on the potential of immune modulators, which instead of acting as inhibitors to “release the brake,” like checkpoint inhibitors, act as agonists to “step on the gas” and rev up the immune system. This is a concept that many Pharma companies are currently looking to explore for new drug development opportunities, for example:

Roche ESMO Media Briefing Immunotherapy Approach

Source: Roche Media Briefing at ESMO 2014 in Madrid

When it comes to combination strategies, the big unanswered questions are which ones will produce big gains in response rates and survival outcomes, and which ones will be duds?  

After all, much like targeted therapies, not all targets will be relevant in all tumour types – it will depend on the underlying immune system.

In New Orleans, Dr Kohrt talked about the potential advantages and concerns around combination strategies and why he’s particularly interested in CD137 as a novel target for immunotherapy.

In-Memorium Holbrook Kohrt 

It is with great sadness that we must report that Holbrook Kohrt is no longer with us. He died, aged 38, on February 24, 2016.

 

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One of the interesting questions raised by the recently announced and much-discussed Juno/Celgene collaboration is whether you really need a Chimeric Antigen Receptor (CAR) T cell therapy in your portfolio to succeed as a global cancer immunotherapy company?

One leading cancer immunotherapy company that believes you don’t is Roche.  At ASCO 2015 I had the privilege to talk about this with a leading cancer scientist, William Pao, MD PhD (pictured below). Dr Pao formerly worked with Nobel Prize-winning scientist Harold Varmus at Memorial Sloan Kettering, and subsequently led the Hematology-Oncology Division at Vanderbilt. He joined Roche in July 2014 to lead their early development of innovative oncology new products (see press release).

Dr William Pao Roche

I particularly enjoyed Dr Pao’s discussion of the T-cell centric strategic framework around which the Roche/Genentech cancer immunotherapy portfolio strategy is based.

If you haven’t done so already, do listen to Episode 3 of the Novel Targets podcast (ASCO Lung Cancer Show) in which you can hear an excerpt from my interview with Dr Pao.

This is the first in a series of interviews with scientific leaders at companies at the forefront of cancer research.

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Immune checkpoint inhibitors that target CTLA4, PD1 and PDL1 can generate prolonged responses in a minority of patients, but the results so far in prostate cancer have been disappointing. Prostate cancer doctors have not been part of the excitement spreading through the cancer community like a “Mexican wave.”

Prostate cancer has not featured significantly in the cancer immunotherapy news recently, but that’s not to say there is not a lot going on. The phase 3 trial results of ipilimumab (a checkpoint inhibitor of CTLA-4) in the pre-chemotherapy setting of advanced prostate cancer (NCT01057810) are expected soon and there is also the eagerly awaited phase 3 trial of the PROSTVAC vaccine (NCT01322490).

Dr James Gulley ASCO 2015

At ASCO 2015, BSB interviewed Dr James L. Gulley, MD, PhD Chief of the Genitourinary Malignancies Branch and Director of the Medical Oncology Service at the National Cancer Institute (pictured above).

He talked about some of the cancer vaccine work he has done as part of the CRADA (Cooperative Research and Development Agreement) between the NCI and Bavarian Nordic, as well as strategies to help immunotherapy work in those tumors such as prostate cancer that are non-inflamed, where there may be an insufficient immune response for checkpoint inhibitors to work effectively.

Readers may recall we interviewed him at ASCO GU earlier year, “How to make non-immunogenic cancer sensitive to checkpoint inhibitors.” His outstanding work could shape the future of prostate cancer immunotherapy.

This post also includes additional ASCO 2015 commentary on from Dr Oliver Sartor, Professor of Cancer Research at Tulane University, who shared his perspective on the ipilimumab and PROSTVAC phase 3 prostate cancer trials that are due to readout soon.

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Have you ever sat in a freezing cold scientific session and been so engrossed in the compelling presentations that followed, you simply forgot to take notes? Not one. That actually happened to me at the American Association for Cancer Research (AACR) in Philadelphia this year in one of the many fringe sessions that I attended.

Reading Terminal Clock

Reading Terminal Clock, Philadelphia

Granted, the hot topic of the conference was undoubtedly checkpoint inhibition, but I was anxious to escape to the comfort of some meaty and familiar basic and translational science, namely MYC.  MYC is largely thought to be a difficult to target, even undruggable protein, and along with RAS and p53, represents a formidable challenge for cancer researchers.  These three oncogenic proteins alone are probably responsible for more drug resistance developing and even death from cancer than any other proteins in a patient with advanced disease.

For cancer patients with advanced disease, the clock is ticking on time they have left.

Solve these three problems (MYC, RAS and p53) and we may have a shot at dramatically improving outcomes. As Dr Gerard Evans (Cambridge) noted:

“I think it’s fair to say that we don’t really know why interruption of any oncogenic signal actually kills cancer cells, but one of the reasons that we’re interested in MYC is because it seems to be a common downstream effector of many, maybe all cancers.”

Sure, the road to success is paved with an enormous graveyard of failures, just as metastatic melanoma was before checkpoint blockade came along, ironically.  What I heard at AACR both inspired and filled me with greater confidence… we’re finally getting somewhere.

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New Orleans – one of the presentations of note at Immunology 2015 (the annual meeting of the American Association of Immunologists) was by Thomas J. Gajewski MD, PhD from the University of Chicago. His presentation on “Innate immune sensing of cancer via the STING pathway” was well worth the trip to New Orleans.

Presentation by Dr Gajewski at Immunology 2015

Readers may recall the post we wrote in March on “What is STING and why does it matter in cancer immunotherapy?” It followed the news that Novartis were collaborating with Aduro Biotech (NASDAQ: ADRO) on agonists that activate the STING (Stimulator of Interferon Genes) signaling pathway in immune cells.

I had the privilege to talk with Dr Gajewski (pictured below) after his presentation at AAI.

Dr Tom Gajewski AAI 2015

Excerpts from the interview will feature on Episode 2 of the Novel Targets podcast (@TargetsPodcast). (Do sign up for the Novel Targets Newsletter if you want to be among the first to know when this will air). Subscribers can read more from the interview below.

You should read and/or buy access to this post if you don’t know the answers to the following:

  • What role does the tumor microenvironment play in response to cancer immunotherapy?
  • How could the tumor microenvironment be a biomarker of response to checkpoint inhibitors?
  • Why target the STING pathway?
  • Reasons Novartis are collaborating with Aduro Biotech?
  • How may a STING agonist be brought to the clinic?

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AAI LogoNew Orleans – At the 2015 annual meeting of the American Association of Immunologists (AAI) leading experts came together to share their insights on the Promise of Cancer Immunotherapy.”

The audience at #AAI2015, in an artic chilled hall, heard from an outstanding panel of speakers, many of whom flew in specially:

  • Immunologic Checkpoint Blockade: Combinations and Mechanisms, Jedd Wolchok (MSKCC)
  • Immune Checkpoint Therapy: Clinical Success and Next Steps, Padmanee Sharma (MD Anderson)
  • Improving Cancer Treatment Through Immunotherapy Combinations: Combination MAb Therapy: Dual tumor & Immune Targeting, Holbrook Kohrt (Stanford Cancer Institute)
  • Curative Potential of T-Cell Transfer Immunotherapy for Cancer, Steven Rosenberg (Surgery Branch, NCI)
  • PD-1 pathway blockade in cancer therapy: new frontiers, Suzanne Topalian (Johns Hopkins)
Dr Steven Rosenberg (NCI)

Dr Steven Rosenberg (NCI)

Cancer Immunotherapy is such a fast-evolving field that at Immunology 2015, we heard data that wasn’t at the annual meeting of the American Association for Cancer Research (AACR), just a few weeks ago.

Several presenters also put in context data that will published at the forthcoming ASCO annual meeting.

If you’d like to hear more about some of the checkpoint inhibitor data at AACR15, do listen to the first episode of the Novel Targets podcast (if you haven’t already done so).

It’s available as a free download on SoundCloud and on iTunes.

This post offers a top-line summary of some of the key messages we heard in the #AAI2015 symposium.

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Continuing our series on the ASCO GI meeting, today marks the end of the conference coverage with an interesting look at overcoming resistance to EGFR therapies such as Erbitux and Vectibix.

One of the hallmarks of EGFR monotherapy in colorectal cancer is stable disease with eventual relapse, but few dramatic responses. This suggests that other factors may play a role in driving oncogenic activity.

Dr Tejpar, Leuven

Dr Tejpar, Leuven

Recently, patient derived xenografts (PDX) have begun to play an increasingly important role in helping to understand the biology of the disease and facilitate improved trial design.

Earlier this week, we discussed the molecular characterisation of the disease based on the keynote talk by Dr Sabine Tejpar. Her group in Belgium as well as others in Italy and Spain have been very active in European translational work in this area to identify and map the pathways influencing EGFR therapy in GI cancers.

What can we learn from the latest findings in this space?

The answer may well surprise you.

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Over the last decade or so, we’ve seen a lot of new targeted agents approved in a variety of different tumour types. Of the big five cancers (breast, lung, melanoma, prostate, and colorectal) one clearly stands out as missing out on exciting new developments in the last 5 years.

In fact, we haven’t really seen anything startlingly new in the colorectal cancer (CRC) space since 2004, when the FDA approved cetuximab (Erbitux) and bevacizumab (Avastin) to much fanfare a few weeks apart at the beginning of that year. Sure, there have been other EGFR and VEGF inhibitors approved since, including panitumumab (Vectibix), z-aflibercept (Zaltrap) and regorafenib (Stivarga) in various lines of therapy, but you could argue that they’re all more of the same (type of inhibitors) and incremental in their improvements, rather truly game changing or disruptive.

Why is this? Why the discrepancy?

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After the recent raft of posts on immunotherapy, it’s time to turn our attention back to oncogenic addiction.  A couple of key topics have dominated colorectal cancer over the years, namely what causes EGFR resistance and why don’t patients with the BRAF V600 mutation do as well with RAF monotherapy compared to melanoma patients?

In today’s post, we take a more detailed look at BRAF mutant colon cancer in terms of what we’ve learned so far and what the potential therapeutic solutions are, which could influence patient outcomes in a positive way.

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Clovis Oncology RociletinibThe potential of Clovis Oncology’s EGFR inhibitor rociletinib (formerly CO-1686) to treat T790M negative non-small cell lung cancer (NSCLC) was one of the interesting talking points of the recent JP Morgan Healthcare conference in San Francisco (JPM15).

At the JP Morgan Healthcare Conference (JPM15), Clovis presented updated data that shows some efficacy in those NSCLC patients who no longer respond to an EGFR inhibitor, but don’t have a T790M mutation (T790M negative).  Both AstraZeneca’s competitor compound, AZD9291, and rociletinib shown considerable activity in those EFGR resistant patients who develop a T790M mutation and it’s likely they will both soon be approved in this indication, based on the encouraging data seen to date.

However, what is surprising and could be a key differentiation factor for Clovis, is if there is sufficient efficacy in T790M negative patients for use of the drug in this indication.

In this post, we discuss the potential of rociletinib in NSCLC T790M negative patients, whether thought leaders might use the drug in this indication, and delve deeper into the science behind the efficacy seen.

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