A bit more news from ASH 2012
Following up on our Immunotherapy post, here is a link to The In Vivo blog’s writeup of the deal struck between UPenn and Novartis to commercialize the CAR (and specifically CART19) technology that we discussed in our last post:
In Vivo highlights this deal as one of its “Alliance” nominees of the year, and it illustrates the race going on among big pharma and biotech to tie up academic assets at an early stage. Indeed other big players tried very hard to secure this technology.
The Btk inhibitor Ibrutinib made its own splash over the last few days at ASH, including startling clinical data in CLL and MCL:
here’s the CLL press release (via FierceBiotech):
and the MCL story off the JNJ website:
Taken together you have to wonder how these competing technologies – orally dosed small molecule kinase inhibitors v ex vivo T cell manipulation – will play out. Add a big dose of new biologics to the mix, and its clear that the field of B cell lymphoma treatment will become a very interesting scientific, clinical practice and commercial landscape.
We start with breaking news from ASH 2012 (http://www.hematology.org/Meetings/Annual-Meeting/) where my old friend and colleague Carl June from University of Pennsylvania has presented remarkable data on the use of gene-modified T cells to attack and clear CD19+ acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL). In addition to the transduction with a chimeric antigen receptor to CD19, the T cells also contain the CD3zeta signaling domain and the 4-1BB costimulatory protein. The work has been well described in the literature (eg. Porter et al. 2011. NEJM. 365: 725-733). Basically a viral vector is used to string together the requisite pieces for transduction of the isolated patient T cells, which are then returned to the patient where they undergo expansion in the presence of antigen (in this case the abundant CD19 present on both lymphoblastic and normal B cells), under the potent influence of CD3 signaling and 4-1BB costimulation.
What has caught the attention of the public is the story of a pediatric patient, nearly lost, having failed all current therapies, and too ill from chemo to receive any more rounds. The story of her remarkable recovery after treatment is compelling and moving – this work represents a dramatic step forward in immunotherapeutic treatment of an advanced cancer.
So lets back up a bit. Cancer immunotherapy can be defined as medical mobilization of the immune system to attack tumor cells in the hope of clearing the tumor in a way that establishes long term protection, ie. tumor immunity. The field is advancing rapidly, with headline grabbing news from ASCO last summer on the use of anti-CTLA4 and anti-PD1 or PD1-receptor antibodies to unleash the immune system – CTLA4 and the PD1 pathway down-regulate immune responses, so by blocking these molecules the immune system goes into overdrive. You can achieve a similar effect by signaling through pathways that upregulate the immune response, like 4-1BB or OX40. An alternative way of stimulating anti-tumor responses is to vaccinate the patient with tumor antigens. This is the strategy behind Provenge, which uses tumor antigen loaded dendritic cells to activate the immune response to treat prostate cancer.
To date, none of the classical immunotherapy approaches has been broadly effective, that is, they help subsets of patients, maybe 25% or less obtain real relief from disease.
Carl June’s approach has reported about a 50% success rate in the small number of patients treated, and this makes sense, since they have combined a tumor antigen specific approach (the CD19-specific chimeric antigen receptor) with immune stimulation through 4-1BB. Its worth noting that the immunotherapy community has been calling for such combo therapies, and many companies are working hard to figure out what combinations make the most sense, and for which cancer types. One mainstream idea is to combine two different immunomodulators, like anti-CTLA4 antibody plus anti-PD1 antibody.
Back to the pediatric patient – a few notes to get us grounded: First, the patient very nearly died from a massive acute immune response when she received the engineered T cells. This “cytokine release syndrome” was triggered by a massive release of IL-6, a potent pro-inflammatory cytokine. She was rescued by a dose of Actemra (aka tocilizumab, an antibody to IL-6). Second, the patient is likely to remain highly immunosuppressed, and its unclear for how long – perhaps for a long time. This is because all of her CD19+ cells, not only the tumor cells but also normal B cells, were depleted, and its possible that enough modified T cells will remain to deplete any normal B cells that develop.
On balance the results are highly encouraging, and have attracted investment from Novartis, which hopes to commercialize the technology
If we take all this together – remarkable success using a combination therapy technique with potent costimulation, but significant challenges in terms of toxicity and potential for immunosuppression, we can ask ourselves what the next steps might look like.
First and foremost the concept of combining a stimulatory boost to the immune system in the context of tumor vaccination should be pushed hard – this may be the simplest way to achieve similar results without having to remove and genetically alter patient cells.
Second the concept of combining immune modulators should be approached with care, as the potential for runaway and dangerous hyper-immune responsiveness is very real (readers will remember the infamous TeGenero anti-CD28 antibody clinical trial). Clinical trial evolution in this are in encouraging, as we are seeing the development of multi-arm adaptive trial designs that allow single and combo agent arms that can advance or be dropped on timely efficacy/toxicity readouts.
Third, in the context of ALL and CLL, the lymphoblastic leukemias treated by Carl June’s team, additional progress will come from the development of highly selective kinase inhibitors – and these too may eventually see use in combination with the therapies discussed above.
Finally its important to remember the tumor specific nature of these advances: each medical advance tackling very specific diseases. It is in this regard that this newest approach may be most important since theoretically one might target other cancers simply by redesigning the chimeric antigen receptor to recognize different tumor antigens. Indeed, this technology is already being developed.
We will update as new results come in.
Introducing the Sugar Cone Biotech Blog
When we consider sources of biotech and pharma intel and insight, we see striking differences in style. Lets look at two very common types of content, then offer an alternative.
Style 1: Wafer Cone Analysis. Short on insight, full of reposts and recycled story lines. This is the most common form of biopharma “news” and clogs the web with redundant traffic. Apt to show up uninvited in your inbox, the Wafer Cone wraps just enough fluff around a bit of information to give the appearance of substance while adding nothing of its own. Cheap or free, of little value regardless.
Style 2: Waffle Cone Analysis. Always too much of a good thing, layering heavy “added value” to otherwise straightforward analysis. Bloated and expensive, the Waffle Cone is the speciality of large consulting houses that churn out commercial analyses of technology development, of clinical stage therapeutics, of medical practice and of the competitive landscape. Characteristics include broad consensus with client’s existing assumptions, a ‘tell ’em what they want to hear’ approach to analysis, and the selective use of supportive quotes from KOL’s. Add a sprinkle of the latest business buzz words and you’ve got it. And its going to cost you plenty.
These are obviously extremes on the spectrum that spans biopharma news, blogs and consulting.
I’d like to define a better approach:
Sugar Cone Analysis. A problem-driven approach designed to capture essential data and provide critical insight to enable action. No more, no less. We track critical trends in drug development, medical research and practice, translational efforts, clinical trial design, and breakthrough technologies. All posted here for open commentary. There are already many excellent science and business blogs that capture content (see who we follow), but we push analysis to generate hypotheses: what will or should happen next. And we’ll check back in to see how our hypotheses fare in the real world.
Through Clarion Bio Consultancy we offer our clients transparent, critical data analysis and its’ impact on the questions at hand. We specialize in helping biotech and academic groups build out research programs and investment clients build out companies. We focus on creating research plans the drive asset momentum, staging programs for investment, and critical assessment of existing programs. We ensure upfront that the questions, underlying assumptions and timelines are clear. Iterative communication ensures alignment on goals and progress. Outcomes and recommendations are presented without prejudice, allowing confident and crisp action.
Contact us for more information: firstname.lastname@example.org