Biotech Strategy Blog

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

Posts tagged ‘nivolumab’

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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Today for the second AACR 2017 Preview, I wanted to switch things up a bit and turn from looking at an important trend to a specific tumour type. One of the reasons for this is that we received questions from readers about recent data presented at medical meetings in this sphere.

It’s also not something that we have covered extensively here on BSB, so looking at something in a different light is often a good idea since insights and intelligence can sometimes jump out afresh.

Given that there are also some important clinical trial results emerging here, this is something we can expect to return to in Washington DC when the data is presented at AACR next month. What can we learn ahead of the event though? It turns out the answer is quite a lot.

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With the advent of single agent checkpoint blockade and success in melanoma, lung and urothelial carcinomas has come the realisation that the majority of patients do not respond and even some that do have a response of short duration. Immune escape and adaptive resistance are not an uncommon occurrence.

There has been much focus of late in looking at ways to address this by uncovering the relevant mechanisms underlying the biology of the disease and this is an avenue we can expect to see more research evolve. We already know that JAK1/2 upregulation and PTEN loss have lead to resistance with checkpoint blockade – what about other possible mechanisms?

Indeed, at the ASCO-SITC meeting in Orlando last week, another such target emerged and clinical evaluation is already underway, making it a worthwhile area to explore.

Here we take a look at the science and biology, as well as the emerging clinical landscape to see which companies are involved and may get a jumpstart on the combination niche.

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As we move from monotherapies to combinations in the immuno-oncology space, we start to see some intriguing ideas being explored from additional checkpoints to vaccines to neoantigens to immune agonists to oncolytic viruses. There are numerous ways to evaluate how to boost or jumpstart more immune cells upfront in the hope of seeing better efficacy.

One way to do this is to better understand the tumour microenvironment.

Wall of people at ASH16 in San Diego

If we know what’s wrong under the hood, we might be better able to make the immune system get going… more gas, faulty starter motor, dead battery, loose wire, broken fan belt? All these things and more might be a problem so you can see that diagnosing the issue up from from basic and translational work might be instructive for clinical trials.

If you don’t know what problem you’re trying to fix or repair then you might as well be throwing mud at the wall. Just as we don’t expect a car mechanic to suggest changing the battery or starter-motor without first diagnosing the issue, so understanding the tumour microenvironment in each different cancer or disease might also be a helpful strategy.

At the recent American Society of Hematology annual meeting (#ASH16), there was a fascinating sceintifc workshop that focused on this very concept – what’s going on under the hood and how do we go about fixing it?

Here we explore these ideas via an interview with a thought leader and specialist in the field. What he had to say was very interesting and candid indeed.

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San Francisco: ASCO Gastrointestinal symposium 2017 – Update on metastatic colorectal cancer

It might surprise quite a few people that colorectal cancer (CRC) is the third most commonly diagnosed cancer globally, especially in the western hemisphere where hereditary, dietary and lifestyle factors can be important.

The bedrock of therapeutic approaches in this disease have largely centred around chemotherapy (FOLFOX or FOLFIRI) along with targeted therapies against EGFR (cetuximab, panitumumab) or VEGF (bevacizumab, ziv-aflibercept, regorafenib etc).

In our second report from #GI17, we take a look at some of the emerging monotherapy and combination approaches that are showing early signs of moving the needle in advanced CRC, an area that has been relatively dormant of late.  This is partly because it’s a cold tumour and with the focus on cancer immunotherapies, it’s not the first tumour type that companies will necessarily rush to evaluate.

Things are changing though, even in colorectal cancer so it’s time to look at some key studies that may teach us more about this disease.

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San Francisco: A look at what’s new in gastric cancer (GC) from the 2017 ASCO GI meeting.

Day 1 of #GI17 is filling up…

There were several phase 3 trials presented in GC and gastro-esophageal junction (GEJ) carcinoma in both targeted therapies and immunotherapies this past weekend.

  • When we look carefully at the latest data, what do we find?
  • Where are the opportunities and challenges in this niche?

Another critical question that many observers will be interested in is…

Will BMS’s checkpoint inhibitor, nivolumab (Opdivo), overcome recent setbacks in lung cancer and make a mark in stomach cancer to challenge approved targeted therapies such as ramucirumab (Cyramza)?

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Challenges and Opportunities in the evolving 1L NSCLC Landscape

Rolling English Landscape in Devon

Following a series of events – from BMS’s failure with nivolumab monotherapy… to Merck’s sudden announcement to file their combination of pembrolizumab plus chemotherapy… to AstraZeneca’s delay of the MYSTIC trial exploring durvalumab plus tremelimumab this week, there’s never a dull moment in lung cancer!

So can we expect some more surprises in store in 1L NSCLC?

I say yes we can!  

The big questions are what are they and what impact will they have?

2017 is ironically, the year of the Rooster – so who’s going to crow loudly at dawn and who is going to get strangled in the process?

In the world of cancer research it is unlikely that everything wins or is successful, so figuring out the early signs and hints is an important part of the process.

One thing I learned early in this business is that it pays for companies to be humble, flexible and open minded rather than arrogant and dogmatic in their thinking… otherwise you can easily be blindsided.

There were a few examples of that in oncology R&D last year, a repeat could very well follow in 2017 for the unwary.

Here we look at 1L NSCLC in the context of multiple phase 3 trials that are slated to read out… from AstraZeneca, BMS, Merck and Genentech.

If you want to know what the potential impact of these events are on the landscape, including what we can expect from MYSTIC, CheckMate-227 and several others, then this is the post for you because some surprises are likely in store.

We cut through the chase to explain the what and the why in clear simple language.

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View of Cambridge and Charles River

Neon Therapeutics is based in Cambridge, MA

One of the much anticipated cancer immunotherapy presentations at the 2017 JP Morgan Healthcare conference was by Neon Therapeutics CEO Hugh O’Dowd.

As readers know we’re riding the Immuno-Oncology wave on Biotech Strategy Blog, and one of the exciting new topics to emerge is whether we can target neoantigens to create personalized immunotherapy.

Our mini-series last year on neonatigens received a lot of attention. It included a primer and three interviews. We were very much of the opinion that Neon Therapeutics is a company to watch out for.

In case you missed them, here are the links:

I highly recommending reading these articles as background on the science and new product development as a prelude to the latest commercialisation update we will cover in today’s post.

What did we learn from the 2017 JP Morgan presentation of the Neon Therapeutics corporate strategy?

If you didn’t make it to the presentation at JPM17 in San Francisco (it wasn’t webcast), you may be interested in this post. This is the latest update in our on-going series on neoantigens and why they matter in cancer immunotherapy.

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John P. Leonard, MD is the Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell in New York. He’s a Lymphoma specialist.

Dr John Leonard at ASH16

Like many hematologists, he’s embraced Twitter as way to share his expertise with others in the hematology community. You can follow him at @JohnPLeonardMD.

Over the last couple of years prior to the ASH annual meeting, Dr Leonard has highlighted 10 lymphoma abstracts that caught his attention. You can tell he gets excellent social media pickup by the fact he’s even generated a hashtag to make them easy to find: #Leonardlist and other hematologists generate conversations around his eagerly awaited picks:

In case you missed them on Twitter, and in the spirit of David Letterman, Dr Leonard took me through this year’s #LeonardList and thoughtfully explained in detail why each selection made the cut… for oncology watchers, the why is often more important than the what.

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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.

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