Biotech Strategy Blog

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

Posts tagged ‘Checkpoint Blockade’

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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Background

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

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.

Great Fire MonumentThe Great Fire of London started 350 years ago in September 1666 following a fire in a Pudding Lane bakery.  It highlights the potential of what a small fire can do once it takes hold – over the course of 3 days, 13,000 houses and 436 acres were destroyed.  It forever changed the landscape of medieval London.

The Monument (pictured right) to commemorate the Great Fire was designed by Sir Christopher Wren. Constructed from 1671 – 1677, it is 202 feet in height, the distance to the bakery where the fire started. You can even walk up it, if you are in the area.

When we think about cancer immunotherapy, one of the emerging important trends is the need to “inflame” or set fire to the immune system, especially in those cancer patients who don’t have a pre-existing immune response.

We want to ignite the immune system, in the hope that it will create the equivalent of the Great Fire…

Great Fire of London Plaque

In this post we’re starting at mini-series looking at neoantigens, beginning with a primer on what they are and why they matter in cancer immunotherapy.  In subsequent posts we’ll look at some of the innovative ways companies are identifying and targeting them.

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The Shard from River ThamesMuch has been written about the impact of cancer immunotherapies, particularly the twin pillars of checkpoint blockade and CAR T cell therapies, but beyond that lies a huge wealth of alternative approaches that may come in very useful indeed.

Just as we have seen oncogenic escape witth targeted therapies, there is also a related phenomenon called immune escape. Likewise, this can occur as either primary or secondary resistance.

It’s very important to consider this issue, because, after all, the vast majority of cancer patients with solid tumours do NOT see durable clinical benefit with immunotherapies when given as single agents. Some don’t respond at all (primary resistance), while others may see an initial response, then relapse (secondary resistance).

Understanding the mechanisms involved in resistance may help us design better combination trials to address the underlying biology as well as develop biomarkers to help select appropriate patients for each regimen. Clearly resistance can vary, not only by tumour type, but also by lesion and patient, making it a very complex situation to research.

Some interesting new information has recently come to light that is worthy of futher discussion and analysis, particularly in the context of other published data in this niche.

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There were so many posters worthy of further analysis and discussion at ASCO this year that we may well need to write a longer series than usual on some of these hidden gems!

ASCO 2016 Posters 6If you’re anything like me, just getting round the massive poster hall melée each day in one piece to nab the QR codes and chat to some KOLs felt like an achievement in itself, never mind having the time to read and digest them properly.  This is why it’s nice to sit down and process some of the findings afterwards because there was actually quite a lot to learn on the nuances with later reflection.

So what’s on deck in the hot seat today?

Here, we focus on the importance of the tumour microenvironment and how that can be manipulated so that subsequent therapy can be more effective.

Fortunately, there are a number of different approaches that can potentially achieve this lofty goal, at least preclinically, but what happens in the real world when these concepts are actually tested in people with cancer?

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We’ve noticed for a while now that trials involving immunotherapies have not just standard adverse events reported, but also immune related adverse events (irAEs).  We saw these articulately in combination trials at ASCO earlier this month.

Most of these have involved colitis, hepatitis, pneumonitis and such like. If the signs and symptoms are picked up early through careful monitoring and education, these can be more easily managed and controlled.

What about auto-immune diseases?

Is there a risk of auto-immune disease with long term use usage of checkpoint blockade, especially in situations where patients may be treated until progression, which could be a long time if the patient is one of the lucky ones who get a durable complete response?

In today’s post we take a look at these issues. To learn more, subscribers can log in or you can sign up in the blue box below:

ASCO 2016 Collective WisdomContinuing part two of our mini-series on colorectal cancer, today we move from the big scale Immunoscore study to small subsets of disease that are looking interesting in several ways.

For years, advanced colorectal cancer has been dominated by chemotherapy (FOLFOX or FOLFIRI) with and without targeted therapies (VEGF and EGFR antibodies), with very little new to talk about. Part of the challenge here is how do you add something the existing standard of care and move the needle significantly. In front-line, for example, the OS is already out 2-plus years, so these are long and risky trials to undertake. Not surpisingly, many companies have sought to evaluate their agents in tumour types where they consider the risk of development to be lower.

Unless… we can find creative approaches that turn the paradigm on its head and identify a clearly defined niche that can be carved out separately from allcomers.

This is where we’re at now – identifying subsets that might respond exquisitely to novel approaches based on a rational understanding of the underlying biology.  One obvious subset might be BRAF, which can be treated with a BRAF inhibitor with or without other targeted therapies as Dr Pietrantonio and colleagues (2016) literally just showed for example, but what about others of potential interest?

Colorectal cancer with microsatellite stable (MSS) disease represents 95% of metastatic patients. These are people whose mismatched repair system is proficient and actively functional in fixing the DNA strand breaks that occur during the course of life.

In contrast, those with microsatellite instability (MSI) are the minority of people with colon cancer (and some other cancers too) whose mismatched repair system is deficient and unable to adequately repair the DNA strand breaks. Ironically, this leads to thousands of mutations that can be recognised by the immune system to help detect the presence of cancer. It also tends to occur in hereditary cancers such as Lynch Syndrome.

We’ve been following the MSI vs MSS story for a while now, but at ASCO this year there was more data available and things appear to be getting clearer on the commercial front too.

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The 10 abstracts selected here are actually not in order of magnitude, preference or weight… with the lone exception #1, an incredible piece of work that was a decade in the making.

Chicago!

Chicago!

Few of these choices are in the press briefing, none are in the Plenary session – they’re often hidden gems that many will miss in the hurly burly of the data drop and noise.

They’re also 10 abstracts that I feel are worthy of highlighting with some additional commentary.

Some of the ideas here illustrate some intriguing trends that are emerging, others may have a big impact on the cancer immunotherapy space, either because of the novel concept idea, or because the data are very compelling, if you understand the science.

You can decide for yourselves – which ones would you pick and why?

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One of the unintended consequences of the rise of cancer immunotherapy has been the fall in interest from patients who might be candidates for entry into clinical trials for other therapies, such as chemotherapy and targeted agents, for example.

St Charles Streetcar New OrleansA number of industry friends have uniformally expressed concern over how difficult it has been enroll such trials and bemoaned the broader – and often not anticipated – effect to the extent that some trials have even been terminated.

This situation often occurs, not because of lack of efficacy or severe side effects, but simply a lack of enthusiasm and low accrual rates. Quite a few patients consider chemo to be nothing short of ‘poison’ and don’t want anything to do with it as a result, unless it can be avoided.

Here’s my advice to those in this situation – stop moaning, start re-thinking, and re-positioning your agent in a different light to the investigators who enroll these studies. If they lack heart, in a highly competitive world, you have to stand out and thus, everything flows from the basic rationale of what you’re trying to accomplish.

What exactly do we mean by that?

Yesterday, we discussed one of the rate limiting steps in the cancer immunity cycle – getting more T cells into the tumours so that that subsequent immunotherapy can be even more effective.

One way to do that?

Chemotherapy!

At AACR recently, we came across some intriguing ideas and approaches that are being discussed and explored, which may open many people’s eyes and minds. It rapidly became clear during discussions with several experts that all is not what it seems, and smart companies are already taking advantage of the new science that is emerging as well as a deeper understanding of the underlying biology of how the immune system behaves in cancer patients.

Here, we offer insights from our latest interview with a thought leader in the field for his perspective on how we can improve response rates and outcomes with cancer immunotherapy.

Fair warning: I must confess that it opened my own mind to fresh ideas and different approaches in an unexpected way – you may experience the same sentiments.

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UNO SignIn our post AACR analysis, I noticed some consistent observations across multiple talks and informal discussions with thought leaders.

Some of these ideas are pretty important and help us see the big picture for the near and medium term future in the cancer immunotherapy space.

The “Claws” sign we saw at the University of New Orleans sums things up!

Without much ado, it seems a good point to capture and summarise these ideas so that readers can compare notes and debate their thoughts too.

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Port Sunglight SpringSpring has arrived in many parts of the world, and with it I am always reminded of William Wordsworth’s classic poem, “I Wandered Lonely as a Cloud:”

I wandered lonely as a cloud 
That floats on high o’er vales and hills, 
When all at once I saw a crowd, 
A host, of golden daffodils; 
Beside the lake, beneath the trees, 
Fluttering and dancing in the breeze.

 

So what does the future hold for cancer immunotherapy?

Inspired by Wordsworth, I’ve sat on my cloud and have looked at some of the recent review papers and thought pieces published by experts in the field. Do they offer a Jerry Maguire – like mission statement: “The Things We Think and Do Not Say: The Future of Our Business” or will we have to wait till AACR 2016 in New Orleans to learn more?

 

This is the latest in our pre-AACR 2016 annual meeting series. Subscribers can login to read more or you can purchase access below.
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