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

Posts from the ‘Immunotherapy’ category

Paris, France – Last week I had the pleasure of attending a two day Immuno-Oncology Summit, an industry sponsored CME event organized by the European Academy of Tumor Immunology (EATI) and Miltenyi Biotec.

The summit was held at the Centre de Recherche des Cordeliers (CRC) in the quartier Latin on the historic left bank of Paris, a short walk away from Notre Dame cathedral.

Paris Immuno-Oncology Summit 2017

Most of the attendees were French researchers so this opportunity afforded them a chance to hear from leading researchers at the forefront of cancer immunology, including several who travelled from the United States to speak at the event.

CRC Courtyard Statue

I have yet to attend a cancer immunotherapy meeting where I didn’t come away with new insights into what is a fast moving field, where it’s important to see “connections” beyond a tumor type or target.

This post offers top-line commentary highlights on five key presentations at the summit. There were two parallel tracks and a lot of interesting speakers at what was an enjoyable meeting, so think of this like a postcard from Paris.

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Over the years we’ve interviewed folks from numerous pharma and biotech companies here on BSB, including those with targeted therapies (small and large), as well as immunotherapies.

Some companies have small pipelines and may be forced by circumstances to explore what they have or seek collaborations with bigger partners.

For big pharmas with large pockets plus broad and deeper pipelines, the challenge is quite different – how do you prioritise potential combinations and tumour targets given it is impossible to evaluate them all in the clinic? How do you create differential advantage and value when you’re relatively later to market compared to your competitors?

In the BSB spotlight this week we have two researchers in clinical development and R&D from the same company, who happen to have both elements in their pipeline in areas of high competition.

Part one of our latest mini-series explores the IO side of the business as we look ‘Through the Keyhole’ at what’s going on in terms of biomarkers, monotherapy trials, combination studies (both IO-IO and IO-targeted) and what to expect in the near-term future later this year. It’s a wide ranging, candid, and fascinating discussion that highlights a lot of potential in terms of what could happen with a large pipeline.

In all, it makes for rather interesting reading and certainly changed how I perceived the company’s efforts in the IO sphere (for the better, I might add).  So what’s fascinating about their approach and what can we learn from their progress to date?

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We’ve been saying for a while that 2017 and onwards would be when we start to see a few IO combination trials start to shake out. Interestingly, that process seems to have already started, if recent news is any thing to go by.

With this in mind, the annual meeting of the American Association for Cancer Research (AACR) coming up this weekend gives us a timely moment to explore combinations that are looking interesting… or not.

In the last of our AACR 2017 Conference Previews, we take a look at what to expect on this year’s program in the IO and Checkpoint arena. In short, it’s quite a lot and not without some controversy either!

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In the first of our 2017 AACR annual meeting previews, we are taking a look at a particular theme that we expect to hear much more about over the coming months.

Washington DC cherry blossoms

In order to make something better than what it is, we first need to step back and understand the various factors that underpin it. To do otherwise is akin to the proverbial throwing of mud at the wall and hoping something sticks.

Trying things out just because they seem like a good idea or that’s all you have in your pipeline doesn’t really inspire the greatest of confidence in a clinical trial’s success.

This is also where several factors including tumour biology, cancer genomics, biomarkers, and acquired resistance can intersect to produce some intriguing results.

Please note that our Conference Preview series are never random.  When looking at the abstracts as a whole, we try to organise them around a particular scientific theme or a tumour type. The idea here is that it makes it much easier for our readers to see and grasp emerging concepts and trends. It’s also a deeper dive into the whys; things happen for a reason – why is that?  What can we learn from the process?

These are also not random selections from say, publicly traded or private companies, big or small caps.

It does take more time to roll thematic articles out, but the advantage is that over the course of the next two weeks readers will be better equipped to get a grip on the meeting ahead of the event.

Indeed, a couple of subscribers even told us last year they learned more from our in-depth previews than they did from the meeting itself because it’s easy to miss the important things or become ‘bigly overwhelmed’ as one bio fund manager explained to me.

Strategically, we’ve taken one specific theme today and explored what we can expect based on what we have learned to date, and looked at how that will potentially impact a few things going forward.

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Sunny Day in Orlando, FL

Orlando, FL was the place to be last week thanks to two specialist meetings in town: BMT Tandem 2017 #BMTTandem17 (joint meeting of ASBMT and CIBMTR), and the inaugural ASCO-SITC Clinical Immuno-Oncology Symposium #Immunosym.  Indeed, several speakers spoke at both events!

Throughout this week we’ll be writing about the insights we gained from the two meetings into the latest data and trends in immunotherapy, immuno-oncology and adoptive cell therapy.

We’re kicking off with cell therapy insights from the BMT Tandem Meeting. It’s the joint meeting of the American Society for Blood and Marrow Transplantation and Center for International Blood & Marrow Transplant Research. If you don’t already, do follow the ASBMT President for 2017-2018 Dr Krishna Komanduri, @drkomanduri. He’s actively involved in CAR T cell therapy trials in Miami.

It’s worth remembering that bone marrow transplanters led the way in the use of immunotherapy to provide cures for cancer. Today, the BMT transplant community are pioneering adoptive cell therapy, and in particular  CAR T cell therapy in multiple hematologic malignancies including ALL, NHL, CLL and Multiple Myeloma. This makes the annual BMT Tandem meeting one to watch for some of the latest cell therapy data.

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One of the frequently cited conceptual frameworks in Cancer Immunotherapy is the Cancer Immunity Cycle developed by Drs Dan Chen and Ira Mellman from Genentech.

Ira Mellman Dan Chen Authors of Cancer Immunity Cycle

Ira Mellman and Dan Chen

As we heard Dan and Ira tell us on the Novel Targets Podcast recorded last year at #AACR16, the cancer immunity cycle doesn’t include all the elements that we now know impact the immune system and whether someone will have an immune response. The microbiome is one example that readily comes to mind.

To address this, Chen and Mellman have now published the next installment in the series in Nature:

“Elements of Cancer Immunity and the cancer-immune setpoint.”

The review paper published last month incorporates the latest research into a different framework that looks at the factors that influence what they call the ‘cancer-immune setpoint.’

Anyone involved with cancer immunotherapy knows how fast moving and dynamic the field is, something they draw attention to:

“The pace of cancer immunotherapy clinical studies is such that they have outstripped our progress in understanding the underlying science. However, this situation has created the opportunity to combine emerging scientific and clinical insights in a synergistic fashion that… will also provide guidance for the identification of new targets… and the crafting of a framework for making decisions on a personalized basis.”

Conceptual frameworks such as those proposed by Chen and Mellman will be of increasing importance as we try to make sense of the tsunami of cancer immunotherapy clinical trial data, including combinations, that is coming our way over the next 18 months.

During my recent visit to San Francisco for ASCO GI, I had the great pleasure to catch up with Daniel S. Chen, MD PhD, (Global Head of Cancer Immunotherapy Development, Genentech/Roche) and talk about his latest thoughts on how we should think about cancer immunotherapy.

In writing these review papers he told me:

“We look at this as an opportunity to really think about the field, and try to conceptualize what is happening.”

We also discussed their collaboration with Kite Pharma, something of relevance to conferences this week as we head off to BMT Tandem and the ASCO-SITC meeting.

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National Harbor, MD

Despite remarkable results with cancer immunotherapy to date, we do need to keep out feet on the ground and remember that response rates are relatively low to modest (10–30%) and the majority of patients do not respond or see a benefit with these approaches.

As we start moving beyond checkpoint monotherapy, the realisation has fast hit many researchers and companies that we really don’t know as much about the tumour microenvironment (TME) as we would like.

No doubt we will learn a lot more about it from the combinatory approaches, but be aware that this also means higher risk associated with such developments – we will likely see a lot of failures – and hopefully, some successes too.

This is where the little biotech companies have an opportunity to shine… they may have some intriguing IO compounds in development but not an anti-PD1/L1 backbone, meaning they can collaborate with a big pharma company to explore novel combinations in small phase 1/2 trials to determine what works or not. This is much lower risk (and R&D costs) for both parties and we get to see more quickly where things shake out.

At the annual Society for Immunotherapy of Cancer (SITC) meeting last week, there was a whole day devoted to New Immunotherapy Drug Development.  

Some of these agents look worthy of watching out for and following their progress.  A variety of data in different targets and MOA were presented from big and small companies alike.  We selected a few of the promising ones for further review and discussion.

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National Harbor Maryland

National Harbor, MD

The range of different types of cancer immunotherapies in the clinic now is fairly broad, with many promising approaches being evaluated.

Cytokines, despite their initial challenges with toxicities, are an essential pillar of this approach, along with checkpoint inhibitors and agonists, adoptive T cell therapy, and now even neoantigen approaches and cancer vaccines.

Nektar Therapeutics ($NKTR) are developing two intriguing immuno-oncology compounds based on cytokines, which are in early development called NKTR–214 and NKTR-255.

The idea behind this approach is that they are immuno-stimulatory therapies designed to expand T cells and Natural Killer (NK) cells directly in the tumour microenvironment, thereby increasing expression of PD-1 on these immune cells.  Subsequent checkpoint therapy could potentially be made more effective. We already know that those patients with few or no T cells are less likely to respond (cold or non-inflamed tumours) so the hunt is on finding ways to address this particular challenge.  Can it be done therapeutically?

Data was presented this past weekend at the Society for Immunotherapy of Cancer (SITC).

Was the data encouraging enough to justify further clinical development or is this a compound headed to dog drug heaven?

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IL–2 therapy with aldesleukin has been shown to be effective in both renal cell carcinoma (RCC) and mestatatic melanoma, including the induction of complete responses. The major challenge though, was severe toxicities requiring hospitalisation and monitoring in tertiary cancer centres with ITU facilities.

At the recent ESMO conference in Copenhagen, I came across an interesting poster on a novel approach to this problem from Nektar Therapeutics. (See: Poster # 1.)

Previous preclinical work exploring the combination with anti-CTLA4 was presented at ASCO earlier this year and demonstrated that the combination deliver durable anti-tumour activity and vigorous immune memory recall (See: Poster # 2.)

The company are developing NKTR–214, an anti-CD122 agonist, which was engineered to induce immuno-stimulatory effects by delivering sustained signals through the IL–2 receptor pathway.  Slow release of PEG chains over time generates active PEG-conjugated IL–2 metabolites of increasing bioactivity, improving PK and tolerability compared to aldesleukin… with fewer debilitating side effects.

Here’s a schematic of how it works:

Source: Nektar Therapeutics

Source: Nektar Therapeutics

NKTR–214 is currently in early clinical development, both as a single agent NCT02869295, with an additional a phase I trial in combination with nivolumab planned.

Nektar had a total of three posters on NKTR–214 at the meeting of interest, which you can explore. (See: Posters # 3, 4, 5.)

They also have several other IO compounds in their pipeline that look intriguing. One in particular, NKTR–255, is in late preclinical development and expected to move into the clinic next year (see Dr Zalevsky’s comment in the interview below.)

This compound is quite different in terms of its target and mechanism of action.  NKTR–255 engages the IL–15Rα/IL–2Rγ receptor complex, stimulating proliferation and survival of CD8+ T cells and NK cells, enhancing formation of long-term immunological memory. This may then lead to a sustained anti-tumour immune response. (See: Poster # 6.)

Clinical Data at SITC

Phase 1 dose finding data for NKTR–214 as a single agent was presented by Dr Adi Diab (MD Anderson). Patients (n=20) with a broad range of tumours were evaluated including RCC, melanoma, bladder, colorectal and other solid tumours.

Dosage ranged from 0.003 mg/Kg to 0.012 mg/Kg given every 3 weeks by infusion. 18 patients were evaluable for efficacy.

Here’s a quick snapshot of the efficacy findings:

  • 12/18 (67%) evaluable patients had stable disease at the initial 8 week scan
  • 7/18 (39%) evaluable patients had radiographic reductions in tumor size per RECIST 1.1 on NKTR–214
  • One patient with metastatic melanoma (prior treatment with ipilimumab and a BRAF inhibitor) has received 13 cycles of treatment (0.003 mg/kg q3w) with stable disease and continues on therapy with NKTR–214
  • Of the 18 evaluable patients, a total of 5 patients with metastatic RCC who had progressed on 1 prior TKI were treated with NKTR–214 at the 0.006 mg/kg q3w dose level:
  • 1/5 (20%) of these RCC patients had a uPR and treatment with NKTR–214 is ongoing
  • 2/5 of these RCC patients had additional tumor reductions of 6% and 10% per RECIST 1.1 while on NKTR–214

Recall in the lirilumab article from SITC earlier this week that in a sample size of up to 25 patients we might hope to see a response rate of 35% to have some confidence with statistical significance.  Here, 39% of the evaluable patients had a reduction in tumour size, which is encouraging for single agent activity.

Dr Diab presented a nice chart illustrating clearly how durable these responses look visually:

Source: Nektar Therapeutics

Source: Nektar Therapeutics

If we see objective responses with monotherapy, and even stable disease, then this augers well for giving a compound in combination with a checkpoint, where we might expect to generate augmented responses.

Adverse Events

  • No immune-related AEs were observed (e.g. colitis, dermatitis, hepatitis pneumonitis, adrenal insufficiency)
  • No grade 4 AEs related to NKTR–214 or deaths
  • No capillary leak syndrome was observed at any dose
  • One patient experienced a DLT of hypotension/syncope at 0.012 mg/kg q3w and continued on treatment at 0.006 mg/kg q3w
  • 3/25 patients experienced grade 3 hypotension, which was rapidly reversed with fluid administration and all patients continued on treatment with NKTR–214
  • Most common grade 1–2 adverse events were fatigue, pruritis, cough, decreased appetite, pyrexia, and hypotension

Tolerability wise, NKTR–214 demonstrated a favourable safety profile with convenient, outpatient q2w or q3w administration in 25 patients evaluable for safety to-date:

What happens in terms of the immune profiling?

  • Increase in total and newly proliferating (Ki67+) CD4+ T cells, CD8+ T cells, and NK cells in 9/9 patients with blood samples evaluated in the trial to date, with increases of up to 30-fold observed
  • Increase in frequency of PD–1+ T cell subsets of up to 9-fold in the blood
  • Increase in CD8+ T cells and Natural Killer (NK) cells of up to 10-fold in the tumour microenvironment in patients with evaluable tumour biopsies (pre-dose and post-dose at week 3), with minimal intratumoral changes to T regulatory cells
  • Increase in expression of cell-surface PD–1 on T cell subsets of up to 2-fold in the tumour microenvironment
  • Induction of an activation gene signature in the tumor micro-environment, including increases of 5-fold or greater in expression of interferon γ, perforin and granzyme B genes
  • Changes in T cell repertoire (TCR) – a measure of T cell clonality – in the tumour microenvironment

In short, NKTR–214 clearly modifies the tumour microenvironment leading to an immune activation gene signature, as demonstrated in the talks:

Source: Nektar Therapeutics

Source: Nektar Therapeutics


Dr Adi Diab

What this suggests to me is an intriguing and novel agent that is much better tolerated compared to what we would expect from traditional IL–2 therapies, with the capacity to sensitise tumours prior to checkpoint blockade.

The critical questions here though, are would a combination turn cold tumours into hot ones, or would it enhance existing nivolumab responses and turn PRs into CRs?

Dr jonathan Zalevsky

Dr Jonathan Zalevsky

To learn more, at SITC this week I also had the opportunity to speak with both the principal investigator and a company scientist.

Dr Adi Diab (right) is an Assistant Professor (MD Anderson Cancer Center) and Dr Jonathan Zalevsky (left), is Vice President Biology & Preclinical Development.

We chatted after their presentation in the “New Cancer Immunotherapy Agents in Development” session.

Interview with Drs Diab and Zalevsky at SITC

Dr Zalevsky: My name is Jonathan Zalevsky, I’m the Vice President of Biology at Nektar Therapeutics.

Dr Diab: Dr Adi Diab, I’m Assistant Professor at the Melanoma Department at the University of Texas, MD Anderson Cancer Center.

BSB: You mentioned IL–2 [in your talk here], obviously we’ve seen IL–2 therapies on the market, particularly in renal cancer and melanoma. My understanding is that the toxicities of those particular therapies are pretty tough to tolerate for patients, so how is this compound different, will it be more tolerable?

Dr Diab: That’s exactly how it’s related to the structure of the cytokine. The cytokine has a pegylation that allows it to be prodrug so an advantage, which means you can give it once every 2 weeks or 3 weeks, which you cannot do with regular cytokines because they are short-acting.

In terms of toxicity, the structure of the pegylation is located to prevent or minimize the activation of the CD25, the alpha subunit of the interleukin receptor 2, and that’s the subunit that has been correlated with toxicities with many of the high dose IL–2 including vascular leaky syndrome or capillary leaky syndrome, which mandates the patients be in the ICU setting, in the intensive care unit.

Minimizing this activity through the NKTR–214 structure allowed us to give these cytokines as an out-patient setting and that’s a huge advantage to be able to give a cytokine in an out-patient setting without worrying about these life-threatening toxicities.

BSB: In terms of the potential combinations, would you look at this as something that will be useful for patients with cold tumors and turn them into a hotter tumor, or more in terms of patients who have a PR who get some response, but don’t make a CR and therefore you could use it to potentially boost those patients. How would you look at this?

Dr Diab: This is an excellent question. One of the biological markers, in all patients that we looked at, these cytokines led to activation of CD4, CD8 cells and Natural Killers.

It will definitely enhance the upfront, first-line therapy to be better because it is a non-overlapping mechanism, it will add in, I would say a synergistic or additive at the minimum, to any checkpoint inhibition. That’s an advantage because it has a non-overlapping mechanism of action.

So if your response rate was, for example, 50%, this may increase significantly based on it’s non-overlapping mechanism. That may translate from PR to CR, but definitely we will have more responders. That is my prediction to that.

Major problem is that the checkpoint refractory population are most of the patients – 500,000 patients die every in the United States because of cancer, most of them do not respond to anti-PD1 or checkpoint inhibitors.

One of the major problems, immune resistance mechanism, is that the tumor does not have the T cells that express the PD–1. If you have a drug that can be safely given, delivering more T cells to the tumor microenvironment, then can we arm with a checkpoint blocker, there is an advantage.

Does NKTR–214 deliver that? Yes, and that’s why we are targeting a refractory population in the combination trial, as well, because this population needs to be benefited and these are most of the cancer patients, and we believe the combination will benefit.

Let me tell you about this population. One patient who was on NKTR–214, he achieved stable disease. When we did the biopsy for him, we see enhanced T cell infiltration into the tumor. We see that there are more CD8’s, less T regulatory cells. We were excited about that. He’s been achieving stable disease for a long time.

In discussion with the patient, we decided to switch to nivolumab, to see if our theory is good.

“Since we achieved the goal of putting T cells into the tumor, we added nivolumab and we achieved a very, very impressive and early response in terms of decreasing the tumor burden of the patient. The patient clinically feels much better and his tumor has decreased in the first scans by more than 50%.”

That really supports the theory that this drug, although by itself it can have significant activity, it really complements and increases the population that can benefit from checkpoint blocker inhibitors.

BSB: In terms of the T cells, we hear quite a lot about T cell exhaustion, as well as the lack of infiltrate, would these cytokines be able to do something for the patient’s who have, essentially, exhausted T cells or is that something completely different?

Dr Diab: Not related to the checkpoint inhibition, one of the things cytokines do is they overcome exhaustion. By itself, one of the things we see [with NKTR–214] is decreasing the threshold of activation of T cells.

For example, when you combine a vaccine with a cytokine, you see much more response to the vaccine, compared to without NKTR–214. That has nothing to do with the checkpoint blockade, but also decrease the threshold of activation, this is the end of other axis of exhaustion.

By all means I think this cytokines can lead to a better profile of the immune system, less exhausted. It doesn’t mean it can replace checkpoint blockade, this is an independent pillar that can complement checkpoint inhibition.

Dr Zalevsky: If I can add to that, the exhaustion is a phenotype that is seen locally in the tumor microenvironment in response to a specific antigen, but then also driven by inhibitory signals that cause the T cell to really become unresponsive to the antigen that it’s supposed to be targeted against.

Now there are some therapies that try to overcome and rescue that by specifically targeting those cells themselves, trying to rescue that phenotype, but the way the cytokines can work is actually completely differently.

They stimulate the brand new proliferation of brand new healthy, fresh cells.

BSB: So these aren’t exhausted T cells?

Dr Zalevsky: They are not exhausted to begin with. And when they come in mass, in large force into the tumor microenviroment, they’re healthy and they’re fit, and they’re able to respond to the tumor, when paired with the checkpoint inhibitor that response is even greater.

That’s one of the best ways we believe to overcome exhaustion is to create a brand new army.

BSB: In terms of giving these in combination, would they be given concurrently or would sequencing matter?

Dr Diab: This is a smart question because the right answer is in a clinical trial to test the sequential things. However, I think because of the length of the drug that can be given every 3 weeks, so it stays in the blood for a long time, we can give it concurrently.

Usually the problem with concurrent is not the efficacy of these things, the problem is adding toxicity, so that’s what we’ve seen with ipi and nivo, anti-CTLA4 and anti PD–1. The toxicity way exceeding the additional benefit.

When you have a cytokine like that, in our safety data we did not see any overlapping toxicity, like a new related toxicity, we didn’t have to give any of our patients immune suppressive corticosteroids, so clearly the toxicity profile is not overlapping with traditional checkpoint toxicities. I think combining it will be safe. Conducting the clinical trial is the right way and we will watch that, but in preparing for that, given this data, I think giving them concurrently is the first way to go, but we are open to look at our data, restructure and see if sequential will be needed at one point. At this point we are confident that concurrent therapy will be safe and will be efficacious as well.

BSB: Will the tumor type matter or is this something that could potentially be broad acting in multiple different tumor types.

Dr Diab: Just to look at the tumor type… The cytokine therapy meant to overcome prediction is actually to enhance and increase the accessibility to the immunotherapy, to more than one tumor.

Tumors that not already set to respond to immunotherapy such as melanoma, renal cell carcinoma and some of the lung cancers, but also to enhance the mobilization of these new fresh T cells, may increase the response rate of immunotherapy in other tumors that not traditionally respond to immunotherapy and that’s why we’re bringing breast cancer and that’s we’re testing them upfront and in the refractory setting in other solid tumors.

Dr Zalevsky: What I’d like to add to that is when you think about the immune system and immune surveillance, it’s totally different than when you think of an immunotherapy to treat an established tumor, established disease.

In the latter case, we look at some tumors that maybe more or less immunological and more or less treatable with these mechanisms, but in you and I that don’t have cancer, no matter where a microtumor is developing, no matter which tissue, which organ, the immune system, the immune surveillance is able to kill it.

So what we are really trying to do with the cytokine therapy is bring the patient back to that healthy condition, let the immune system be unleashed again, let it fill up the tumor no matter where the tumor is, no matter which tissue, no matter which organ and give back that kind of immune surveillance that you seem to have lost as you progress into the later and later stages of disease.

To that question, we think there will be many, many tumors that can be unlocked with this therapy and bringing in NKTR–214, particularly with checkpoint combination, will make many, many tumors available for therapy.

BSB: In terms of clinical development, where are you now?

Dr Diab: We are just about to complete our phase 1 dose-escalation trial, identifying the recommended phase 2 dose and I think we have identified which dose we want to go in terms of combination.

We are just about to start the combination trials with nivolumab in collaboration with BMS. We will target first-line and refractory in melanoma, so target those population, improving the first-line but overcome and rescuing those who do not benefit. Same thing for lung cancer, we’re going to target second-line therapy because nivolumab is approved there.

Bladder cancer we’re going to target first-line therapy as well, we’re going to try that. Renal cell carcinoma we’re going to try second-line therapy, as well as triple negative breast cancer, we’re going to have second-line therapy as well to approach that.

We’re hoping that by the end of this year we’ll have a couple of patients already treated on that combination trial, gearing towards that.

BSB: Do you plan to have data for ASCO next year?

Dr Diab: This is ambitious. I think we will have some patients – remember it’s not enrolling the patients, but you will have to have response. However, I should say that it is very important for any combination therapy that you also demonstrate safety. Trials of anti-CTLA4 and anti-PD1, in the first 6 patients we already knew that this is going to be a toxic regimen.

We will hope at least by ASCO – since the deadline is usually early February/end of January – we will have some preliminary safety data, who knows, maybe we will have some efficacy data, I am always optimistic to that, and I would like to share that. It is a tight timeline for us to achieve it and we will report what we have.

BSB: Do you have any other immunotherapy products in your pipeline that you can combine with this?

Dr Zalevsky: Absolutely, so we’re really interested in cytokines and cytokine approaches. We’ve been working on another related cytokine based off on interleukin–15 (IL–15). So IL–15 interacts with part of the signalling machinery that IL–2 does, but it works in a different way. It engages a different alpha receptor, not the CD25 that Adi was talking about, but a different IL–15 receptor.

That has functions where dendritic cells can express IL–15 directly to T cells in the presence of cell-cell contact. What we are finding in our studies of IL–15 is that it has very significant and potent effects on the memory cell compartment particularly in CD8 T cells, where it can stimulate proliferation and protection of survival in effector memory, stem cell memory and central memory compartments.

We’re also seeing that in the presence of heavy antigen stimulation, IL–15 by inducing the expression of an anti-apoptotic protein called BCL–2, protects those cells from death due to overstimulation of the antigen. This is very, very important when you think about the kind of overall duration and durability and strength of anti-tumor immune responses.

We want to allow those cells to be alive as long as possible and proliferate and expand against that antigen as long as possible, to not limit their contraction… more persistency, longer durability, longer duration of action.

We’re also finding that that protein has very, very profound effects on the natural killer cell compartment as well. So it has a very nice complementarity to the NKTR–214 molecule. There’s a good rationale for using them together, which we’ve also been able to uncover preclinically.

BSB: Exciting times for you!

Dr Zalevsky: Absolutely, we’re targeting next year as an IND for that product, NKTR–255.


Additional Commentary

Following on from the phase I monotherapy trial, Nektar now have a collaboration with BMS to investigate the combination of NKTR–214 with nivolumab in advanced solid tumours such as melanoma, RCC, NSCLC, bladder and triple negative breast cancer (TNBC).

The patient populations (n=260) include first line, second line, IO naive and IO relapsed. This should give plenty of opportunity to elucidate where the combo can be optimised. Data is expected over the next 18 months.

The initial results from the pilot patient given nivolumab after NKR-214 offer an encouraging proof of concept that requires further validation in a larger sample of patients.

In terms of the deal, it appears to be an exploratory clinical collaboration for now since Nektar reatin all the rights to NKTR–214 and split the clinical costs of the trials. Prior to September 2018, if Nektar chooses to partner NKTR–214 then BMS has the right to first negotiation. Nektar retains the right to conduct its own trials of NKTR–214 with any anti-PD1/L1 agents and can collaborate to run clinical trials with other companies outside of anti-PD1/L1.

Recall that checkpoint blockade (or indeed any therapy) works best when there are more T cells in the tumour as opposed to none or even exhausted ones. Based on the immune profiling seen in the NKTR–214 study at SITC, I would say that the ability to increase the supply of fresh fit CD8+ T cells into tumour along with NK cells augurs well for improved efficacy with the combination over either approach alone.

Cancer Immunotherapy will require personalized treatment based on the type of cancer you have, and the immune response your body has generated to the cancer.

Dr Holbrook Kohrt Stanford

Dr Holbrook Kohrt at Immunology 2015

The sadly missed and visionary Dr Holbrook Kohrt was very prescient when he told BSB in New Orleans back in May 2015:

“Today when I see a patient or you go to a cancer center, the first thing they ask is what type of cancer do you have? Most patients respond – breast cancer, a colon cancer – unfortunately we are not in position where patients can say I have a deficiency in my cytotoxic CD8 cells or I have overly active regulatory T cells.

I actually envision a day when patients will know both sites, they will know they have breast cancer and they’ll also know it’s because there’s a lack of effector cytotoxic CD8 T cells. That combination knowledge, of what your immune system is lacking and what tumor you have, that combination will allow you to identify what type of immunotherapy you need.

Patients may need CAR directed T cells and those will be for patients who have completely non-functional T cells themselves, no matter what therapy you give them, you’re not going to create those cells within the body, therefore you need to do it ex-vivo in a petri dish and give it back to them.

Other patients may have T cells that just need to be turned on and so all they need is a checkpoint modulator and that combination is going to be effective enough for them.

So it’s this dual diagnosis, diagnosing their immune system and diagnosing their tumor that’s going to allow us to identify one, two, or three therapies that’s going to be the right cocktail.” 

See post: Holbrook Kohrt leads the way in Targeting CD137, you can also listen to excerpts on the Novel Targets Podcast: Episode 6: Stepping on the Gas

ICYMI do listen to the tribute to Dr Kohrt on the Novel Targets Podcast from two people who knew him at Stanford: Dr Ron Levy and Dr Dan Chen (@DanChenMDPhD). It’s at the start of Episode 11: Cancer Immunity Cycle.

Immunoscore® — a diagnostic test based on the immune profile of a patient is based on the pioneering work of INSERM scientist Dr Jérôme Galon.

Dr Jerome Galon at ASCO 2016

Dr Jérôme Galon at ASCO 2016

We are fans of his work, and interviewed him at the 2015 European Cancer Congress. See post: Immunosurveillance, Immunoscore & Personalized Cancer Immunotherapy – an interview with Jérôme Galon.

Over 10 years ago, Dr Galon’s research published in The New England Journal of Medicine and Science showed that the type, location and density of immune cells within a tumor predicts clinical outcome in early stage colon cancer.

These findings led to the development of an assay called Immunoscore® that’s based on an analysis of cytotoxic T cells, the ones that kill cancer.

In the process, it has led to a new way of classifying stage 2/3 colon cancer patients: those with a high Immunoscore® (good prognosis), and those with a low Immunoscore® (poor prognosis). Dr Galon’s work has shown that irrespective of whether you are MSI high or MSS, colon cancer prognosis correlates with Immunoscore.

Dr Bernard Fox at #AACR16

Dr Bernard Fox at AACR 2016

As we heard from Dr Bernie Fox (@BernardAFox) at AACR 2016. See post: AACR Cancer Immunotherapy Insights from Dr Bernard Fox, listen to excerpts on Novel Targets Podcast Episode 12: Of Mice and Men:

“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.”

Immune response is key to outcome, which means that knowing what your immune profile is will be key to deciding which of the many immunotherapy options, either alone or combination will achieve the desired effect.

A large multinational phase 3 clinical trial sponsored by the Society for Immunotherapy of Cancer (@SITCancer) was set up to validate Immunoscore® as a biomarker in Stage 2 colon cancer.

Dr Galon and co-authors reported the results at ASCO 2016. See post: immunoscore validated as an important biomarker for colon cancer. He featured on the ASCO 2016 episode of the Novel Targets Podcast: Immunotherapy or Bust.

Immunoscore® is now being commercialised by Marseille based HalioDx(See post: HalioDx CEO Vincent Fert outlines commercial strategy for Immunoscore in US and Europe).

ciml40During a recent visit to the Marseille Immunopôle for #CIML40, I had the pleasure to do an impromptu tour of the HalioDx lab.

When listening/watching this, do bear in mind this was not a scripted tour, and also the people I spoke to were speaking English as a second language.

It’s not intended to be a definitive guide; if you are a patient you should talk to your doctor about any questions you have about diagnostic assays such as Immunoscore.  At the moment, it’s only available for research or clinical trial use, but HalioDx has plans to make the assay commercially available on the US and Europe.

The company has more information on their website and also recently published a paper in the Journal for Immunotherapy of Cancer (open access) that describes how the test is done in more scientific detail.

In the meantime, subscribers can login to join me for a lunch-time tour, or you can purchase access below. The audio-slideshow tour was for several weeks open access and available to all, but is now for subscribers only:

ciml40-marseille-luminyThere is a lot of interest in manipulating the microbiota to improve clinical outcomes – there was a whole session dedicated to it earlier this week at the CRI-CIMT-EATI-AACR international cancer immunotherapy conference in New York.

At the recent scientific meeting to celebrate the 40th anniversary of the Centre d’Immunologie de Marseille-Luminy (CIML40) in the South of France, Dr Eric Pamer spoke about his research into microbiota-mediated defense against intestinal infection.

Dr Eric Pamer presenting at CIML40

Photo Credit: ATGC Partners

Dr Pamer is an infectious diseases expert at Memorial Sloan Kettering Cancer in New York, where he runs a laboratory (The Eric Pamer Lab) focused on the role of the microbiota in immune system development and in defense against antibiotic resistant pathogens.

The gazillions of bugs in our gut, collectively the microbiota, interact with the innate immune system.

Researchers have shown that the effectiveness of antibiotics and the type of immune response we generate depends on the type of bacteria and their diversity in our gut.

ciml40Readers may recall the interview we did with Dr Marcel van Brink (@DrMvandenBrink) at the Society for Immunotherapy of Cancer (SITC) 2014 annual meeting, where he talked about his research into how gut bacteria can impact survival post allogeneic bone marrow transplant. See post: Can you reduce Graft Versus Host Disease GvHD by regulating gut bacteria?

Almost a year ago in November 2015, researchers and the pharmaceutical industry were both galvanized by work from Laurence Zitvogel and Tom Gajewski labs, published simultaneously in Science. See post: Gut Bacteria Impact Checkpoint Inhibitor Efficacy.

Not only could the results from mice experiments be influenced by the gut bacteria they had, but the microbiome could also impact the effectiveness of checkpoint inhibitors.

You can listen to Dr Gajewski on Novel Targets Podcast summarize the research from his lab published in Science. Link to Episode 9: Targeting the Microbiome.


Next year’s European Society for Blood and Marrow Transplantation Congress (#EBMT17) will be held in Marseille.

Given the impact the microbiome has on post-transplant GvHD and survival, I expect we’ll hear more about this at the Congress. Marseille is well worth a visit if the opportunity presents.

Marseille Vieux Port

In case you missed them do check out our recent posts from the Marseille Immunopôle and #CIML40:

In the meantime, our latest expert interview with Dr Pamer covers his wide ranging thoughts on a number of issues, including the impact of the microbiota on the innate and adaptive immune systems and where he sees the field going in the future.

Subscribers can login to read more about his insights or you can purchase access below.

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