Much has been written about the success of checkpoint blockade in solid tumours over the last couple of years with the advent of anti-CTLA4 therapy (ipilimumab/Yervoy) for metastatic melanoma followed by the more recent approval of the anti-PD-1 antibodies in advanced melanoma (pembrolizumab/Keytruda and nivolumab/Opdivo) and lung cancer (nivolumab).
What about hematologic malignancies though?
At the recent American Society of Hematology (ASH) conference, we heard about the first clinical data for anti-PD1 antibodies in patients with refractory classic Hodgkins Lymphomas (cHL) and saw some impressive results. Interestingly, though, the early preclinical work was conducted in mice looking at CTLA4 blockade in a variety of tumours, both solid and liquid.
Is there a rationale for targeting CTLA4 in leukemias, lymphomas and even myeloma? New data presented at a medical meeting in patients with heavily pre-treated and relapsed disease post stem cell transplantation suggests that this might be feasible.
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Recently, Merck have been on a roll in the immuno-oncology space, with the announcement that their anti-PD–1 antibody, pembrolizumab (Keytruda), beat out BMS’s anti-CTLA4 antibody, ipilimumab (Yervoy) in a Phase 3 head-to-head frontline trial in metastatic melanoma. The two primary endpoints of OS and PFS were met and the trial will therefore be stopped early based on the IDMC recommendation. No further details are available until the presentation.
The data from the KEYNOTE–006 study is being presented at the annual American Association for Cancer Research (AACR) next month in the opening plenary session by Dr Antoni Ribas (UCLA).
While it’s nice to see evidence that one checkpoint inhibitor is potentially superior to another, in the long run, combinations are likely to be the best way forward. This approach is more likely to yield improved responses in immunogenic tumours, but also to make non-immunogenic tumours more responsive, thereby improving patient outcomes further.
This begs the all important question – what hints from new emerging data can we glean that will help us figure out novel combination approaches with checkpoint inhibitors?
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Some really intriguing news was announced this morning, with Aduro Biotech issuing a press release on their new global collaboration with Novartis for their “immuno-oncology products derived from its proprietary STING-targeted CDN platform technology.”
Many readers will recall Aduro for its program that inserts genetically engineered lysteria into therapeutics aka the LADD regimen. The lead program, CRS–207, in combination with GVAX Pancreas in pancreatic cancer previously received Breakthrough Therapy designation from the FDA. Their scientific advisers include Drew Pardoll and Frank McCormick, who are immunotherapy and protein pathway specialists, respectively.
The collaboration with Novartis is for a completely different platform based on cyclic dinucleotides (CDNs), which are small molecules that are naturally expressed by bacteria and immune cells and have been recently shown to activate the STING (Stimulator of Interferon Genes) signaling pathway in immune cells.
So what’s the significance of this exciting deal and why does it matter?
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Today I’m answering recent questions from readers, in this case on checkpoint inhibition and where this field is going in the near future.
No doubt we can expect to hear a lot of new data and research being presented at the upcoming AACR and ASCO conferences, so this is a timely point to reflect on a few topics of relevance.
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As we’re coming to the end of our European Association Urology (EAU) coverage for 2015, I wanted to discuss at a rather more quirky, off-the-wall topic and look at one of the gems from the poster halls at this conference.
This year, it’s the turn of urothelial bladder cancer (UBC), a topic that doesn’t usually get much coverage or respect when it comes to new product development. Part of the challenge is the need for new targets to aim at because the particular patient population doesn’t tolerate high dose chemotherapy very well.
At ASCO last year, perhaps the surprise (and most stunning) data of the meeting was the anti-PDL1 checkpoint data (Genentech’s MPDL3280A) in refractory UBC, a disease where there are a lot of elderly and frail patients who are challenging to treat in many ways. This certainly put more attention on the disease and raised awareness to the potential opportunities for new, targeted and altogether more benign approaches to treatment. Subsequently at ESMO last fall, we also saw early data for an anti-PD1 antibody (Merck’s pembrolizumab) in advanced urothelial cancer.
Checkpoint blockade is not the only potential way to treat UBC though, so what other novel therapeutics are in development in this space?
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We’ve been following the updates on the PREVAIL study evaluating enzalutamide (Xtandi) versus placebo in metastatic castrate-resistant prostate cancer (CRPC) in the pre-chemotherapy setting for a while now. It’s interesting to see how the data evolves over time as it becomes more mature.
The first presentation, back in January 2014 at ASCO GU by Dr Tom Beer (OHSU) reported on the first 540 deaths and was subsequently followed by an update of the survival data at AUA in May of the same year by Dr Chris Evans (UCLA).
This morning at the European Urology Association (EAU) in Madrid in the late breaking session on prostate cancer, the honour fell to Professor Bertrand Tombal (Leuven), who did a very nice job of reviewing the mature PREVAIL data (based on 765 deaths) and providing some context for how the CRPC landscape is being impacted by AR pathway inhibitors.
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At the last count, the renal cell carcinoma (RCC) space is quite competitive with five VEGF inhibitors (sunitinib, sorafenib, axitinib, pazopanib and bevacizumab), two mTOR blockers (temsirolimus and everolimus) and not forgetting IL–2, all approved by the FDA for the treatment of advanced disease.
Much of the recent focus has been on sequencing, exploring combinations (generally too toxic with little added benefit), and evaluating the potential for novel immunotherapies in development such as checkpoint inhibitors. Biomarkers are few and far between, making it hard to rationally decide which therapy each patient should get and in which sequence.
The key question is, why is this tumour type so challenging from a clinical and scientific perspective?
Recently, new data has begun to emerge that may help inform or enable us to switch to new approaches. While the urologists are eagerly watching the live surgery on the EAU cam, we highlight research data presented at the European Association of Urology (EAU) in Madrid and take a look at how the underlying biology of RCC can elevate our knowledge about where the potential future strategies and blueprint might lie, if we want to facilitate exciting new developments in this field.
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Here’s something interesting and heart warming to reflect on at the end of a long week:
“Cellular therapy of Epstein-Barr virus (EBV)+ posttransplantation lymphoproliferative diseases (PTLD) in cord blood transplant (CBT) recipients is limited by lack of donor access and the donor’s naive neonatal immune system. We therefore used partially human leukocyte antigen–matched third-party in vitro expanded EBV-specific cytotoxic T lymphocytes (CTLs) to treat 2 CBT recipients with life-threatening, donor-derived monoclonal EBV+ diffuse large B-cell lymphomas with extranodal involvement developing in the context of graft-versus-host disease. Both patients had failed immunosuppression taper and rituximab. After 5 and 9 infusions of 106 EBV-CTL/kg, respectively, each patient achieved a sustained complete remission without toxicity or graft-versus-host disease. Each is alive without recurrence at 20 and 15 months, respectively, post–EBV-PTLD diagnosis.”
Barker et al., (2010) Blood
Viral reactivation post-transplant is potentially life threatening, yet here is a fascinating case study where two young patients were treated effectively and are still alive today.
Atara Biotherapeutics $ATRA announced yesterday (press release) that data from their collaboration with Memorial Sloan Kettering on cytotoxic T lymphocytes against Epstein Barr Virus (EBV-CTL) will be presented at the forthcoming AACR annual meeting. Readers will recall the therapy obtained FDA Breakthrough Designation earlier this month.
So what’s the real story behind this novel approach and how can T cells be used in ever more creative ways? Is there a market opportunity and who are the key players in this space?
Be warned this is a long read, and took us a while to put together. It contains insights from two thought leaders as well as our commentary and analysis. Grab yourself a cup of coffee……
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Over the last few years we’ve heard a lot about the evaluation of predictive biomarkers for checkpoint inhibitors, in particular the value of using PD-L1, whether on immune or tumour cells, as a way of separating responders and non-responders to therapy with anti-PD1 or anti-PDL1 blockers. The results to date have been mixed, with some KOLs concluding that smoking history or number of mutations was more useful in lung cancer and others believing that their assay has better utility.
Some cynical observers I’ve come across have even asserted that companies don’t want to see biomarkers emerge because that then limits their opportunity for patients being treated. Ouch! I don’t believe this to be true, it’s highly complex science and there is much about the healthy immune system that we still don’t know, never mind under more complex situations such as cancer. This is an ever-evolving field about which we still have much learn.
Eventually, we may see further refinement of these approaches, at least in some tumour types and I’m particularly looking forward to hearing more about those advances at ASCO and ASH later this year when the clinical and translational work is more mature.
Next month heralds the annual meeting of the American Association for Cancer Research (AACR). As we noted in our first AACR Preview on Immunotherapy last week, it’s the first time immunotherapy has literally dominated a largely preclinical and scientific program of this nature.
Over the next week or two, will be be highlighting and explaining some of the emerging trends in more detail.
On the important topic of biomarkers, one new approach particularly caught my eye in the abstracts that were released yesterday is worthy of further discussion since it could have important implications to future clinical approaches.
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One of my favourite meetings of the year in our conference calendar is the American Association for Cancer Research (AACR) annual meeting, which is held in the spring. In years past, the agenda at this event has set the scene for the rest of the year in terms of emerging new trends, particularly with regards to targeted therapies. In the last two years though, this hasn’t been the case, as adjusting to the brave new world of immunotherapies has taken some time.
The good news is that AACR has come roaring back in 2015 with a star-studded line-up that includes some of the big hitters and sluggers in the cancer immunology space.
What’s in store for this year, you may well be wondering, and where are we likely to see the new trends evolve?
We took an in-depth look at what’s hot in immunotherapies and where the new directions are going in this latest conference preview, the first one in series relating to the AACR annual meeting being held in Philadelphia from April 18–22nd (Twitter #AACR15).
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