Monthly Archives: May 2014

Thoughts while browsing ASCO abstracts

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SOME THOUGHTS GOING INTO ASCO

The other day I highlighted the anti-CD22-calecheamicin antibody drug conjugate inotuzumab ozogamicin (IO) in adult ALL. There were two interesting aspects of this clinical study. First were the results obtained in de novo ALL setting in which the overall response rate (ORR) was 95%, all scored as Complete Responses (CR), although some with incomplete platelet recovery (CRp). Such response rates are typical of first-line ALL response to therapy, so that was not so surprising. It was nice however to see a reduction in the dose and cycles of chemotherapy used, suggesting that IO may really be able to improve standard of care, assuming the toxicity is no worse than intensive chemotherapy. More impressively, relapsed refractory ALL patients responded well to IO treatment along with low dose chemotherapy. In this setting any current treatment is considered salvage therapy and generally has a very low success rate. In the clinical study with IO the overall response rate ORR was 75%, all CR, CRp or CR with incomplete cell recovery (CRi). 6 month progression-free survival was 87% and 6 month overall survival (OS) was 74%. These are dramatically better results than are usually obtained in this patient population and perhaps approach the responses seen with chimeric-antigen-receptor (CAR) cellular therapies and CD3/CD19 bispecific blinatumomab (link). As we’ve written extensively about this subject we will return to it once we see the IO results at ASCO on Saturday afternoon (abstract #7019).

Recent work giving immunotherapies in context of other therapeutic approaches shows the value of non-concurrent treatment, that is, giving first one therapeutic and then the other. We can assess this approach using several different tumor types. A recent paper in JCI (link) illustrated this approach using mouse  models of solid tumor growth as well as analysis of patient derived tumor samples. In the context of treatment with the anti-EGFR antibody cetuximab, an IgG1 isotype antibody, in both animal models and patient samples, NK cells in contact with cetuximab-coated tumor cells were shown to have upregulated CD137/4-1BB expression. Application of an agonist antibody to 4-1BB induced NK cell cytotoxicity and recruited CD8 positive T cells that recognized the tumor. In the animal models and in cell based assays, the use of anti-4-1BB agonist antibody following cetuximab treatment was synergistic. In the setting of a phase 0 clinical trial it was noted that patients express different levels of 4-1BB on NK cells found within tumors. The level of expression correlated with FCgRIII alleles in patients, with those expressing high affinity FcR having the highest increase in 4-1BB expression following cetuximab infusion. The authors predict that efficacy of the agonist antibody to 4-1BB will stratify based on expression level. This is a very nice bit of work, and recommended reading.

The concept that we can use an immunotherapy to augment the therapeutic impact of a targeted therapy has wide application. Much attention has focused on combinations of immunotherapies such as anti-PD-1 and anti-CTLA4, and we will see a lot of this data at ACSO. Perhaps as interesting however is the use of specific immunotherapies with various other classes of therapeutics. For example, at ASCO we should results from a number of immunotherapy/targeted therapy trials. For example, abstract #2511 presents the results of Phase I study of the BRAF inhibitor dabrafenib +/- the MEK inhibitor trametinib in combination with anti-CTLA4 antibody ipilimumab in BRAF V600E/K mutation–positive unresectable or metastatic melanoma. This is an interesting study as it makes use of inhibitors of a known oncogenic mutation (BRAF V600) and a known resistance mechanism (MEK signaling) and combines these with immunotherapy. The double and triple therapies appear to be well tolerated, and there was no sign of liver toxicity (as was seen in an earlier trial of the BRAF inhibitor vemurafenib plus ipilimumab that resulted in G3 ALT elevations). Preliminary efficacy data are expected at the meeting. Abstract #5010 details the use of the anti-PD-1 antibody nivolumab with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC). The small molecule VEGF inhibitors sunitinib and pazopanib have some efficacy but limited duration of response (DOR) in mRCC. So the question will be two-fold: can we get response rates up, and will they become more durable. We may also hear preliminary results of the use on anti-PD-L1 antibody MK-3475 plus lenalidomide in relapsed/refractory Multiple Myeloma (abstract #TPS3117), and with pazopanib in advanced RCC (#TPS4604) among others (note here that the TPS designation denotes “trials in progress” so you never can be sure what clinical results will be available). These types of trials, grinding through the available therapeutic tools, are apt to give us a glimpse of future clinical practice.

So those are some of the themes we will be building on at ASCO. We’ll also follow up on ADCs, bispecific approaches, some old favorites (e.g. anti-CD20 antibodies), and some novel immune therapeutics. Finally, the focus on immunotherapy has been a bit of a distraction so I want to note that we will update on the use of small molecule inhibitors targeting leukemia/lymphoma signaling and survival pathways, focusing on ibrutinib, idelalisib, ABT-199, IPI-145, etc.

stay tuned.

SugarCone Biotech LLC will be at ASCO 2014

#ASCO14, News

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SugarCone Biotech LLC will be represented at ASCO by Paul D Rennert, Founder & Principal of the Company. SugarCone is actively sourcing innovative therapeutic programs that address unmet needs in cancer treatment. Our goal at ASCO is to continue to build upon our deep expertise in understanding the drug development landscape across tumor classes. While we focus intently on biologics and immune checkpoint therapeutics, we also have intensive experience with small molecule drug development programs. This unique breadth of clinical expertise, deep tumor biology experience and comprehensive understanding of different therapeutic classes has placed us in the center of the recent surge in successful cancer drug development. Specifically, SugarCone brings programs to partners who are committed to the clinical development of important new therapeutics. We also specialize in working closely with preclinical companies to nurture and mature their drug development programs in order to effectively address the evolving clinical landscape.

We have been very pleased to see our clients successfully develop partnerships with top tier biopharma, including Celgene, Bristol-Myers Squibb and Immunogen. Such success provides well-deserved validation, and the capital to build for the future.

Contact us at info@sugarconebiotech.com or cell/text us at 1-508-282-6370.

See you in Chicago!

 

Targeting TNFRs with agonist antibodies for cancer therapy: 4-1BB, GITR, CD27

#ASCO14, 4-1BB, biologics, CD27, CLDX, GITR, immunotherapy, Merck, monoclonal antibodies, OX40, Pathways for Drug Development, Pfizer, TNF receptors

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One of the puzzles in thinking about the available costimulatory receptors on T cells (and NK cells) is the unsettling number of them. Sticking just to the TNF receptor superfamily (TNFRSF) we have OX40 (discussed earlier), 4-1BB, GITR, CD27, and also the TNF receptors themselves (1 and 2), the lymphotoxin beta-receptor, HVEM, and TNFRSF25. There may be some I’ve forgotten. As noted in part 1 OX40, GITR, 4-1BB and CD27 are evolutionary cousins, as are their cognate ligands. Why did the immune system evolve such a complexity of T cell costimulators?

The answer is not entirely clear although the expression patterns and kinetics of expression suggest some rationale for understanding the number of different receptors. Also, as it’s understood that all the TNF receptors signal via NF-kB, Jun and p38, we might see these receptors either compete (for signaling proteins) or cooperate. All of the available genetic and pharmacologic data suggest they cooperate or even synergize, thereby powering the T cell response when needed. Since T cell responses (and immune responses generally) are so dangerous when dysregulated, the multiplicity of on and off switches presumably allows for redundancy of control.

As we said previously, OX40 comes on slow and easy, starting about 12 hours after TCR stimulation, and riding along for up to 96 hours. This is in vitro, cell culture data … so lets recognize that in vivo, in response to the chaotic presentation of antigen, the population of T cells is likely to be turning over, proliferating … so it’s unlikely we will see a finely tuned kinetic response in the real world, as regards the population of responding cells. Nonetheless we can focus on a single T cell, just the one. And we’ve guessed it will be expressing OX40 say from day 2 to day 5 after activation. Lets ignore the fact that activated effector T cells are likely dividing more rapidly than every 5 days, and just ask the simple question – of the other TNFSF receptors, what else is expressed and when, and on what T cell and other cell types?

Cue 4-1BB.

4-1BB is also expressed following T cell activation, and is expressed on other cell types also. 4-1BB expression come up much more quickly after T cell activation, within a few hours, and wanes after several days. This receptor is critical to supporting activated T cell proliferation, differentiation and survival. Expression on T cells may be coincident with OX40, but the consequences of engaging the receptor with an agonist antibody are different. 4-1BB preferentially supports the proliferation and survival of CD8+ T cells, although at least in some settings the activity of CD4+ T cells is also stimulated through 4-1BB. Much of the anti-tumor activity of 4-1BB agonist antibodies in preclinical studies can be traced to stimulation of NK cells although this depends of the tumor type and model used. Less well understood is the role on 4-1BB on other cells types. This receptor is also found on DCs, macrophages, granulocytes, and Tregs. Expression has also been described on vascular endothelium and on some tumor cells. The role of 4-1BB is confusing, with various studies showing expansion of the Treg subset and others suggesting that 4-1BB dampens Treg responses, perhaps via direct effects on DCs. The 4-1BB gene-knockout mouse shows aspects of autoimmune disorders (at least in the mouse strains tested), suggesting a role for 4-1BB in maintaining immune homeostasis following activation. 4-1BB knockout mice have trouble handling tumor challenge, and at least some spontaneously develop B cell lymphomas as they age. It is all a bit complicated.

Regardless, there are two antibodies that can provide some early clinical data. Bristol-Myers Squibb (BMY) started development of the BMS-663513 antibody quite early, before the immunotherapy wave had really gotten started. BMS-663513 is a specific anti-4-1BB agonist antibody, isotype IgG4. The antibody ran into toxicity issues in a phase 2 trial of metastatic melanoma in 2011, leading to a halt of three trials with that antibody. As the toxicity was correlated with dose, BMY has restarted the clinical campaign with BMS-663513, now called urelumab to establish a safe and efficacious dose. A monotherapy trial is being run in patients with advanced/metastatic solid tumors or with relapsed/refractory Non-Hodgkin Lymphoma (NHL). A second trial in NHL is being run in combination with rituximab treatment. A third trial in advanced/metastatic colorectal and head and neck cancers is being run in combination with cetuximab (anti-EGFR). Pfizer’s (PFE) PF-05082566 is an agonist anti-4-1BB antibody (IgG2 isotype). One trial is listed at clinicaltrials.gov, a 3×3 dose escalation phase 1 trial run as monotherapy in patients with advanced cancers, and as combination therapy with rituximab in NHL.

At the June ASCO meeting there will be updates on both the BMY and PFE programs. BMY has a presentation focused on mechanism of action and biomarker analyses. Abstract #3017 outlines the goal of monitoring the immune status of 4 patients prior to and during the phase 1 study of urelumab (BMS-663513: clinical trial NCT01471210). The antibody was given every 3 weeks and the analysis presents results through 3 cycles. PBMCs were isolated from whole blood, and stimulated for 4 hours with PMA/ionomycin to activate lymphocytes. There was an increase in CD8 T cells up to 41% and NK cells up to 62%. CD4 T cells decreased by as much as 23% and regulatory CD4 T cells decreased by as much as 18% comparing the 3rd cycle to baseline. The results are consistent with a preferential impact on CD8+ T cells and NK cells. The level of the cytokines GM-CSF and IFNgamma were increased.

The PFE study (abstract #3007) describes very early data from clinical trial NCT01307267. Patients received PF-05082566 IV every 4 weeks (one cycle) with an 8 week period for assessment of dose-limiting toxicity (DLT) and radiographic analysis of tumor burden (RECIST 1.1). 27 patients were up to 0.3 mg/kg, the highest dose reported in the abstract. The majority of patients had either colorectal cancer (n=11) or Merkel cell carcinoma (n=6), the rest were a collection of solid tumor patients and 2 patients with B cell lymphoma.  25/27 patients completed the DLT assessment period (first cycle). No DLT was established but only 7 patients remain on therapy. All discontinuations from treatment were due to disease progression. A best overall response of stable disease was observed in 6 patients. No duration data is supplied.

These two early trials suggest that safe dose levels can be achieved, that a mechanism of action can be confirmed (urelumab: expansion of CD8+ T cells and NK cells), and that some clinical response can be observed (PF-05082566: stable disease). That’s a pretty good picture coming out of Phase 1. As preclinical data suggest that 4-1BB is most effective in various combination formats, it will be interesting to monitor advances in the rituximab and cetuximab co-therapy arms of these trials. Several potent combinations arising in the preclinical literature include 4-1BB with immune checkpoint inhibition (CTLA4 or the PD-1 pathway) and in combination with agonist OX40 antibody therapy.

Lets get back to the Treg cells, whose function is to suppress immune responses, primarily those of CD4+ T cells. These express 4-1BB constitutively, although it’s not clear how or if they are responding to treatment with agonist anti-4-1BB antibodies. Let’s turn to a different pathway known to have a profound effect on Tregs, the Glucocorticoid-Induced TNFR Related gene (GITR). GITR was first identified as a regulatory T-cell marker and was shown to play a critical role in breaking T cell tolerance by direct suppression of Treg activity. The preclinical evaluation of GITR produced some very striking data, including in combination settings in which anti-GITR antibodies essentially synergized with other immune checkpoint therapeutics to eliminate established tumors. Such combinations have included PD-1 blockade and CTLA4 blockade. GITR agonism is also synergistic with chemotherapy in preclinical models. Clinical development of GITR antibodies has been slow. A program initiated at TolerX and reborn at GITR, Inc., is recruiting for a phase 1 trial in advanced melanoma and other solid tumors. The antibody is TRX518 (NCT01239134). Merck is advancing a phase 1 study with the anti-GITR antibody MK-4166, although this trial (NCT02132754) is not yet recruiting patients. Review articles have mentioned an ongoing clinical program at MSKCC – this is one of the three sites enrolling patients in the TRX518 trial.

To the extent that the driving mechanism of action (MOA) of GITR stimulation is shown to be downregulation of Treg activity, this pathway should be a good candidate for combination therapy with 4-1BB, OX40 or CD27 agonists (see below) as well as with the CTLA4 and PD-1 pathway antagonists. If the MOA in human cancer patients is different or more complex than proposed, different combinations may be more or less attractive.

One last receptor – CD27.

The costimulatory molecule CD27 is constitutively expressed on most effector T cells, memory B cells, and an NK cell subset. So its expression may also overlap with those of the other receptors. CD27 appears to be important for sustained T cell effector function and also the development of T cell memory. CD27 is a marker of memory T cells, conversely, it is low or absent on Tregs. More broadly, CD27 supports germinal center formation that drives B cell maturation and the differentiation of plasma cells that produce high affinity antibodies, and is also important in driving the cytolytic activity of some NK cells.

Although there is a large preclinical literature on CD27 and its ligand CD70, there are few antibodies in clinical development. There are several historical explanations for this I think. CD70 is expressed at high levels on certain tumor types, particularly renal cell carcinoma (RCC). Much effort has gone into the development of cell-depleting antibodies targeting CD70. This expression pattern also called into question the relevance of CD27 in controlling tumor growth, as the ligand would be expected to stimulate immune responses. We now know that RCC and other solid tumors expresses high levels of PD-L1, and likely disables immune responses via this pathway. Not surprisingly then, one of the ongoing clinical efforts is a combination trial of nivolumab, the anti-PD-1 antibody from BMY with CDX-1127, an anti-CD27 antibody from Celldex (CLDX) in a collaboration announced by the 2 companies last week. In the meantime we have 2 abstracts from CLDX at ASCO in June to look forward to. In a 3×3 phase 1 dose escalation study of B cell lymphoma patients the drug was well tolerated with weekly IV dosing, and there were signs of clinical response, including a durable complete response in one patient with advanced refractory disease (abstract #3024; clinical trial NCT01460134). In the same trial, solid tumor patients were treated in a dose escalation phase and then an expansion phase (RCC and melanoma). The drug was well tolerated, there were preliminary signs of clinical response, and measureable activation of the immune system (Abstract #3027). With the potential to support memory T cell differentiation, CD27 may provide an important additional signal to drive long term tumor control. We’ll have to wait and see.

So, we have 4 receptors with overlapping activities and we have multiple antibodies in various stages of development. There will be plenty to learn about these targets and their roles in the future of combination immunotherapy. One of the most promising paths forward is the analysis of immune checkpoint and costimulatory proteins on tumor infiltrating lymphocytes (TILs). It seems very likely that the makeup of the tumor cell defense against the immune system will diverge between tumor types, and perhaps between patients with the same tumor types, or even with the same patient tumor at different times, or in different metastatic locations. Profiling TILs, and perhaps sentinel lymph nodes, for the expression patterns of lymphocytes and antigen presenting cells is likely to help guide combination therapy.

We’ll come back to that. And we’ve not forgotten those NK cells either.

stay tuned.

Targeting TNF receptors with agonist antibodies for cancer treatment: OX40

immunotherapy, monoclonal antibodies, OX40, TNF receptors

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In Part 1 we introduced the evolutionarily related TNF receptor superfamily receptors OX40, 4-1BB, CD27 and GITR (link). All of there receptors are being targeted for cancer therapy due to their ability to stimulate CD4+ and/or CD8+ T cells while potentially shutting down T regulatory cells (Tregs).

The receptor OX40 (CD134) is expressed primarily on CD8+ T-cells, NK cells, NKT cells, and neutrophils. OX40L is expressed on dendritic cells (DCs), B-cells, and macrophages, and at sites of inflammation (e.g. activated endothelium). The expression pattern suggests a critical role for OX40L/OX40 is supporting immune responses. Additional information on the role of this pathway comes from the analyses of expression kinetics upon immune cell activation. OX40 is transiently upregulated on activated CD4+ and CD8+ T cells after engagement of the T cell receptor (TCR). The window of expression is from ~12 hours through ~96 hours, after which the receptor is downregulated. This receptor therefore functions to support the survival and expansion of already activated effector T cells. Importantly, OX40 agonism also reactivates the memory T cell population.

Clinical trials using a mouse anti-OX40 agonist antibody were spurred on by impressive results in preclinical tumor models, both as single agent therapy (in immunogenic tumors) and in combination with chemotherapy and irradiation. Various other combination therapies have since been tested preclinically, and that work is continuing. Early clinical trials with anti-OX40 agonist mAb show that the therapeutic is well tolerated, and have provided evidence of immune system stimulation and modest signs of clinical activity. 

The latest clinical update I can find is from the SITC meeting in November 2013 (link). In a poster entitled “Phase I/II clinical trial of anti-OX40, radiation and cyclophosphamide in patients with prostate cancer: immunological analysis”, Andrew Weinberg’s group from the Providence Cancer Center, Portland, OR report out as follows. The Phase 1/2 trial was run in chemotherapy and hormone therapy-resistant metastatic prostate cancer patients (mCRPC). The therapeutic anti-OX40 antibody was given in three doses, on top of radiation therapy and escalating doses of cyclophosphamide. Expansion of CD4+ T cells, CD8+ T cells and NK cells was observed. This observation supports the hypothesis that OX40 agonism promotes the proliferation and survival of activated T cells, the proposed mechanism of action. In mice OX40 signaling also supports the differentiation of activated T cells into memory T cells that are required for long term protection. There is no corresponding human data yet. There was no expansion of the Treg subset (FoxP3+) except at the highest dose of cyclophosphamide. There were transient changes in circulating PSA, and 5/9 patients, metastatic lesions were stable during the course of the study. Importantly, given that we know that T cells must first be activated in order to express OX40, monotherapy may not be the best setting for testing anti-OX40 agents.

This is a promising start that gives us a few things to think about: 1) PSA was not a useful biomarker, at least in this patient cohort, although larger sample sizes may help sort this out; 2) the immune response was measured in the peripheral blood, not from TILs recovered from the tumors – be nice to see that data; 3) there were no DLTs and the therapeutic appeared safe.

Given that some of the most provocative data being generated around this pathway is in the setting of combination immunotherapy, those trials can be expected to start over the next few years. A combination trial of anti-OX40 plus ipilimumab (anti-CTLA4) in metastatic melanoma was recently withdrawn. It was to be run by the Ludwig Institute for Cancer Research, as sponsored by AgonOx. The rights to the program have gone to Medimmune/AstraZeneca and this may simply reflect a desire to proceed with a better anti-OX40 antibody (the current one being a mouse antibody). If anyone knows the back story here please share in the comments.

OX40 agonist antibodies are a hot commodity. Some recent deals involving OX40 assets are shown below:

Screen Shot 2014-05-18 at 10.10.29 AM

Importantly, all of these deals involve human or humanized antibodies. This should reduce the anti-drug responses seen in the early Phase 1/2 trials that limited dosing.

No doubt there are other deals in the works. The level of activity is driven by the early clinical observations, the apparently favorable toxicity profile, and key advances in the preclinical literature. Several examples of interesting preclinical results include the data demonstrating that anti-OX40 antibody can deplete Tregs directly via engagement of Fc-receptors. The degree of depletion in this mouse model was correlated with the intensity of expression of OX40, with the highest expression found on intra-tumoral Tregs. This is an interesting finding although the translational relevance remains unclear as human Tregs only OX40 when activated through the TCR, and even then expression levels are lower than in mouse. Further, other studies have shown that anti-OX40 antibodies can activate Tregs in mouse tumor models, so there is certainly some complexity here. An attractive hypothesis is that the degree of depletion/activation of Tregs depends not only on the degree of OX40 expression but also the biophysical properties of the antibody (potency, valency, composition of the Fc-binding domain).

Also of critical interest (as mentioned above) will be the utility of anti-OX40 in combination therapies. Preclinical data suggest that OX40 agonism is synergistic with CTLA4 blockade (ipilimumab), PD-1 blockade, 4-1BB agonism, IL-2 cytokine treatment, and targeted small molecule therapeutic drugs. This is rich landscape and we anticipate an explosion of clinical data as fully human anti-OX40 antibodies begin moving through clinical trials.

anti-what? Introducing the next generation of immunotherapeutics.

immunotherapy, monoclonal antibodies, TNF receptors

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Part 1: Introduction to agonist antibody therapies. 

The headlines tell the tale: Pfizer initiates a Phase 1 with anti-4-1BB, Medimmune/AZN advances anti-OX40, Celldex pairs anti-CD27 with Bristol’s nivolumab, and Merck plans a Phase 1 study for anti-GITR. Its very early days for this collection of targets, and I think many people find them difficult to differentiate. As always, differentiation will come in the clinic, but this is a long road. We plan to briefly summarize the biology of this family of therapeutic targets and review their clinical application to date.

First of all it’s worth noting that these 4 TNF receptor superfamily members are closely related, as shown here based on sequence alignment of the cysteine-rich domains as analyzed by the late Jurg Tschopp and his colleague Pascal Schneider, our great friends from the early days of TNF and TNR receptor superfamily discovery:

Screen Shot 2014-05-17 at 8.54.43 AM

The image is from Bodmer et al. 2002 TiBS 27: 18 – 26 (Jean-Luc Bodmer was a member of Jurg’s group at the University of Lausanne). This analysis aligns the CD27, 4-1BB, OX40 and GITR receptors with CD30 and CD40, and places these next to the BAFF/APRIL receptors BCMA, TACI and BAFF-R. Not all alignments produce the same neighbors but multiple independent analyses, including one published by Alexey Lugovskoy (Merrimack Pharma) and myself in 2003, cluster these 4 critical receptors.

Notably, these are all primarily T cell receptors, although that observation alone oversimplifies the biology quite a bit. The table below summarizes the expression pattern of the receptors and their ligands.

Screen Shot 2014-05-17 at 9.04.57 AM

All 4 receptors function to promote and expand CD4+ and/or CD8+ T cell activity. Most also act on NK cells and NKT cells. To some variable extent, signaling through these receptors blunts T regulatory cell (Treg) activity as we will discuss for each target. The therapeutic hypotheses are therefore that activation of these pathways by agonist antibodies, alone or in combination, will trigger anti-tumor immune responses by supporting effector T cell activity and limiting Treg activity. A good set of hypotheses supported by robust preclinical data sets and some early clinical trial work. We’ll look more closely at the development of antibodies to these targets in part 2.

The future of cancer immunotherapy?

AACR14, immunotherapy, TCR therapy, TILs

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Matthew Herper posed a provocative question the other day while discussing CAR T technology: is this how we’ll cure cancer? (link).

Lets look at another example that promises to evoke the same question. Back in April, Steve Rosenberg gave a remarkable talk on the subject of patient-specific tumor-infiltrating-lymphocytes (TILs). We covered this talk in an earlier post (link). Today Dr Rosenberg further exemplified this personalized immunotherapy approach, via a case report in Science (link).

The patient had a highly metastasized gastrointestinal epithelial cell tumor called a cholangiocarcinoma. The patient had been through multiple rounds of chemotherapy, relapsed, and was enrolled in a clinical trial (NCT01174121). Lung metastases were isolated and subjected to whole exome sequencing. At the same time, these tumor samples were processed to derive TILs. The data from the sequencing identified multiple gene (and therefore proteins) that were mutated, and and expression constructs were used to determine if any of the mutated proteins were recognized by the TILs, which would proliferate when stimulated by interaction with antigen. Remarkably, a peptide fragment of the mutated ERRB2IP protein stimulated CD4+ Th1-type T cells in a HLA-restricted manner. These T cells were then expanded ex vivo.

The patient first received an expanded, activated TIL pool containing about 30% CD4+ T cells reactive to the mutated ERRB2IP protein. 40 Billion (yes, ‘B’) T cells were administered along with IL-2, a cytokine that keeps T cells alive and proliferating upon activation. The reactive TILs persisted for many months after administration and impacted the tumor, reducing tumor volume and inducing stable disease (a defined clinical endpoint). Ex vivo stimulation of recovered TILs demonstrated strong expression of the T cell activation receptors 4-1BB and OX40, and the secretion of the cytokines IFN-gamma, TNF and IL-2. The patient maintained tumor regression for 13 months, at which point metastases were observed in the lungs. A second infusion of activated TILs was given. In this case  >95% of the TILs were reactive to the mutated ERB2IP protein. 10 Billion cells were administered. The patient then experienced a tumor regression that was maintain and progressive over time, up to and including 6 months post-administration (the last timepoint provided in the report).

This is an exciting step, moving immunotherapy into a class of tumors that are stubbornly resistant to many immunotherapeutic agents. A few interesting questions arise: 1) would induction of a CD8 response have an additive impact on the tumor? 2) would use of an agonist antibody to OX40 or 4-1BB synergize with this technique? 3) What was the immunosuppressive phenotype of the tumor and metastases, and could this information be exploited in the context of immune checkpoint blockade. 4) How often will metastases reflect the mutational landscape of the parental tumor (or other metastatic clones)? 5) Can the TIL technique be wedded to CAR T technology?  I suppose there are many questions and issues.

This is a great next step in the rapid evolution of oncology treatment, and I’m looking forward to seeing much more.

stay tuned.

Merck’s MK-3475 Deals: Assets, Risk and Innovation in Immunotherapy Pipelines

AbbVie, Astra Zenenca, Bristol Myers Squibb, immunotherapy, Merck, monoclonal antibodies, Novartis, oncology, Pfizer

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The recent news that Merck will aggressively partner the anti-PD-1 program MK-3475 with competitors Pfizer and Amgen, and biotech Incyte, was a welcome recognition that the immunotherapy landscape is too vast and complex for most companies to handle alone. Companies that will succeed in this space over the long haul will position themselves to “sample” many assets and technologies, particularly in combination settings. Why? First, because many combination therapies will fail or be too toxic to use, second, therapeutic modalities will evolve rapidly or be replaced, and third, personalized oncology practice will fragment patient populations.

Merck’s anti-PD-1 antibody MK-3475 is an example of the first generation of immune checkpoint inhibitors, for which we have clinical data. Other first generation therapeutics are ipilimumab (Vervoytm) approved for the treatment of metastatic melanoma, and nivolumab, an anti-PD-1 antibody moving toward regulatory submission this year, both from Bristol Myers Squibb. There are other anti-CTLA4 and anti-PD-1 pathway antibodies in clinical development, just a bit behind, including antibodies to PD-L1 from Roche (RG7446) and Astra Zeneca (MEDI-4736) and to CTLA4 from Pfizer (tremelimumab). It is fair to say that Merck has generated intense buzz around the MK-3475 program, driven by excellent clinical data and an aggressive approval strategy.

If we look over the details of the Merck collaborations we see a convergence of technologies around combination therapy. The Merck/Amgen collaboration centers on developing the oncolytic vaccine T-Vec in combination with MK-3475. The therapeutic hypothesis is relatively straightforward. The immune response to vaccines built using tumor antigens is blunted, in part, because of the immunosuppressive signals induced by PD-L1 expression on tumor cells. So blocking PD-L1/PD-1 mediated immunosuppression may allow a more robust immune response to anti-tumor vaccination strategies. I’ll note here that Amgen recently reported Phase 3 results from their T-Vec trial in metastatic melanoma, hitting the primary clinical endpoint of durable response but just missing the secondary endpoint of improving patient overall survival, which is an endpoint that the immune checkpoint inhibitors do hit. So Amgen has clear motivation here to combine T-Vec with immune checkpoint inhibitors. In addition to the collaboration with Merck, Amgen also has a collaboration with Bristol-Myers Squibb to clinical evaluate the combination of ipilimumab and T-Vec in metastatic melanoma.

The collaboration between Merck and Incyte is also focused on disabling immunosuppressive signaling, in this case as mediated by inhibition of indoleamine 2,3-dioxygenase (IDO), a pathway that regulates T cell responses by depleting tryptophan from the local tumor environment. IDO also appears to regulate T cell activity in lymph nodes draining the tumor site. IDO inhibitors promote T cell effector function while reducing the immunosuppressive activity of T regulatory cells. Incyte’s IDO inhibitor INCB24360 is in Phase 2 clinical trials in metastatic melanoma and in ovarian cancer. In this case then we are considering the potential of dual immune checkpoint inhibition, blocking PD-1 and IDO simultaneously. Incyte already has a Phase 1/2 trial in metastatic melanoma of INCB24360 in combination with ipilimumab and a Phase 1 trial in late stage melanoma in combination with a tumor vaccine.

Merck’s MK-3474 collaboration with Pfizer is very interesting. A phase 1/2 combination trila with axitinib a VEGFR-selective multi-kinase inhibitor (Inlytatm), will be run in renal cell carcinoma. Axitinib is approved as second line therapy in kidney cancer, but the drug has limited potential as a long term therapy and has struggled to distinguish itself from the older multi-kinase inhibitor sorafenib (Nexavartm, from Bayer/Onyx). It is very hard to guess what such a trial will yield, but such combinations of targeted therapies (kinase inhibition in this case) and immune-checkpoint modulators will have to be tried. A recent example, combining ipilimumab and the BRAF inhibitor vemurafenib (Zelboraftm, from Roche) in metastatic melanoma induced unacceptable liver toxicity and was stopped after only four patients had received the combination. Ipilimumab and nivolumab have very different toxicity profiles, and attempts at different combinations are certainly warranted.

The collaboration between Merck and Pfizer also includes development of the combination of MK-3475 with Pfizer’s PF-05082566, an agonist anti-4-1BB antibody. 4-1BB is a potent immune stimulatory pathway that acts by boosting T cell activity. Of interest, PF-05082566 is already in a Phase 1 solid tumor (as monotherapy) and B cell lymphoma (as dual therapy, with Roche’s anti-CD20 mAb rituximab). Finally, Merck and Pfizer have an second agreement to investigate the combination of MK-3475 with palbociclib, a CDK4/6 inhibitor that recently showed encouraging data in advanced breast cancer, although without yet demonstrating an impact on overall survival. These types of combinations are designed to give that precise boost in efficacy, allowing at least some patients the benefit of long term responses that impact disease progression and survival.

Merck’s internal immunotherapy pipeline is thin but as we noted the other day they are beginning to target other pathways, in part via the Agenus/4-Antibody platform deal.

I titled this post “Risks, Assets and Innovation in Immunotherapy Pipelines” because Merck’s efforts around MK-3475 illustrate some clear themes in this space. One, already mentioned, is that going into this space solo is something no company, except perhaps Bristol Myers Squibb (BMY), can contemplate. Even BMY reached outside the company recently to license an anti-KIR antibody from Innate Pharma and to partner with Five Prime Therapeutics on antibody discovery. Why is BMY in such a dominant position? They were innovative (CTLA4 biology) and they have multiple assets including antibodies to CTLA4, PD-1, LAG-3, KIR, 4-1BB and PD-L1, with more on the way. Note that I’m not saying that BMY’s anti-PD-1 antibody nivolumab is better or worse than Merck’s MK-3475, nor do I much care which gets approval first, a race that lots of folks are watching. No one horse will win this field, which brings us back to assets and pipelines.

Beyond BMY, companies like Merck are aggressively partnering because as the immunotherapy field was developing they were less innovative, took fewer risks, and therefore have fewer assets in this space. Companies like Pfizer and Novartis that spent the last decade chasing one oncogenic mutation after another down the rabbit hole found themselves very quickly on the outside looking in. They are now buying and partnering to build portfolios.

And that’s just fine; further, this should be a “pull” environment that motivates the biotech community to generate an abundance of assets. Small biotechs are classically trying to be innovative (to differentiate), take risks (to return dollars on investment) and therefore develop new assets. These are the fundamentals that should drive further expansion of the immunotherapy portfolio across the industry. So how is biotech doing in this new landscape? It is a mixed picture. There is a dearth of new first and second-generation immunotherapeutics, a space that I believe should be asset-rich. This is why Five Prime, 4-Antibody and Costim were all able to do healthy deals relatively early in their development – there is just not a lot of competition.

What happened? Why aren’t there half a dozen anti-PD-1 and anti-PD-L1 antibodies looking for partners, or a dozen agonist antibodies to 4-1BB, OX40, and GITR, and multiple inhibitors of TIM-3 and Lag3? I think this is a case of history repeating itself. After remicade and etanercept were approved, biotechs ran from the TNF inhibitor space, all believing, incorrectly, that they would never be able to compete. Seven TNF inhibitors later, this class still dominates the rheumatoid arthritis market. I wonder if small biotechs are reluctant to follow-on with additional antibodies to the first and second-generation immune checkpoint space because they think they are “too late” – in other words, the value proposition is too risky. If so, I believe they are wrong. The appetite is clearly there, with large biopharma and antibody engineering companies hungry for assets to pull into their pipelines.

Instead, many small biotechs are trying to stay well ahead on the innovation curve, chasing new targets. The problem, as always, is that no one wants to fund that work, because the risk is very high. So the answer is to try to balance innovation and risk in order to create assets that investors will fund. Its a tricky proposition, but essential to biotech’s ability to continue contributing to immunotherapy, and driving value creation. That said, there are some terrific innovative programs out there, in the hands of focused and smart small companies. In the meantime, there are more companies seeking validated assets than there are good programs developing these assets. SugarCone Biotech spends a lot of time building strategic programs for biotechs and a lot of time matching quality assets with partners and investors, so we see this first- hand.

Why else would we need more assets? Straight off, the existing immune checkpoint antibodies ipilimumab and nivolumab induce some terrific responses, but the response rates could be improved. Second, development of the existing combination therapy of ipilimumab and nivolumab has been tricky, with excellent efficacy but troubling toxicity. Note here that BMY can tinker with the dosage and dose schedule of each agent in such combination trials, because they own them both. Less asset-rich companies seeking to develop combination therapy strategies either have to partner their programs (Merck, as discussed here, but AbbVie might be another good example), or acquire everything they can afford (Novartis).

We’ll be watching closely.

stay tuned.

Paul D Rennert, Founder of SugarCone Biotech, joins MedPro Investors

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We are very pleased to announce that Paul Rennert, Founder and Principal of SugarCone Biotech, will join MedPro Investors LLC of New York as a Strategic Advisor, focusing on opportunities in Immuno-Oncology and related fields.

We think that MedPro Investors vision is unique. “MedPro considers companies from seed stage to maturity.  We welcome unique opportunities from private or public companies anywhere in the world and at any stage of development.   If a company’s technology significantly advances the standard of care, and its valuation is realistic, it may be a candidate for MedPro investment.” See more at the MedPro Investors website, http://www.medproinvestors.com/#

The addition of the MedPro Investors LLC group to our network of collaborators further broadens SugarCone Biotech’s work with companies and investors seeking assets in the critical immunotherapy space. We are committed to helping biotech and academic groups develop such assets, building preclinical plans that move with urgency to reach critical experiments and milestones. We then get these programs in front of our investment clients. SugarCone Biotech is actively sourcing excellent assets in immuno-oncology. Please contact us at info@sugarconebiotech.com or at rennertp@gmail.com if you would like us to consider specific programs.

A Conversation with Agenus Leadership

biologics, immunotherapy, oncology, Uncategorized

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Recently I had the opportunity to talk with Robert Stein, CSO and CMO, and Garo Armen, Chairman and CEO of Agenus Inc. (NASDAQ: AGEN). Agenus, formerly Antigenics, broke into the public eye earlier this year with their acquisition of 4-Antibody AG (4-Ab), a privately held European biotech. This week they announced a two-target deal with Merck, using the 4-Ab platform for the generation of novel antibodies to two undisclosed Merck checkpoint targets. These targets are in addition to the six internal checkpoint modulator programs, a quite positive development. This alone makes the company worth a look.

On the other hand a large Phase 3 trial of GSK’s MAGE-A3 vaccine in lung cancer failed, and this vaccine uses AGEN’s saponin-based adjuvant. That was certainly seen as a negative, although there are still 20 clinical programs using AGEN’s saponin-based adjuvant at GSK, Pfizer, and J&J, including GSK’s malaria vaccine that is heading toward Regulatory filing this year. While the company has its fans and detractors among stock analysts, our focus is on the science; so let’s see where that leads us. My conversation with AGEN leadership was wide-ranging but focused on the future of the company, particularly goals and near-term milestones.

I’ll start with the 4-Ab deal, which was touted in February for its transformational potential (adding checkpoint modulators to a vaccine company), and also financials, featuring a modest upfront with most of the value back-ended. The deal brought multiple immune checkpoint programs into AGEN- 6 programs in total. That’s quite a haul. Less well appreciated I think was the 4-Ab antibody platform, branded Retrocyte Display. The technology is interesting. According to the 4-Antibody website, Retrocyte (Retroviral B lymphocyte Display) is a “high throughput cellular antibody expression platform … to allow expression and screening of full-length immunoglobulin antibody libraries in mammalian B-lineage cells … Libraries of full length immunoglobulin heavy and light chains are encoded by separate retroviral expression vectors within B-lineage cells to yield efficiently and stably expressed fully human monoclonal antibodies on the surface of the B-lineage cells in the form of B-cell receptors. Retrocyte Display can be used to directly screen combinations of antibody heavy and light chain libraries for antigen-specific binders.”

This is the platform Merck sought to generate antibodies for two of their targets. Importantly the deal financially supports the R&D work that will be ongoing at AGEN to carry out their end of the collaboration. This is in addition to a potential $100 million in milestone payments and royalties on product sales. Considering that Merck brought proprietary checkpoint targets to the collaboration, participating in the upside is somewhat atypical. This deal makes a statement regarding how much Merck valued accessing the platform and of course it also sets the stage for future platform deals.

Back to those assets, Dr Armen stated quite clearly that the company will internally develop the first tier of antibodies acquired in the 4-Ab acquisition, with a stated goal of moving development candidates targeting CTLA4 and PD-1 and selected additional immune checkpoint modulator programs to IND filings with a target date of approximately 2 years. One of the uses of least some of the immune checkpoint modulators might be to “turbo-charge” the company’s long-standing tumor vaccine programs. These have certainly struggled to gain traction, as have nearly all vaccine plays in oncology, for reasons we now understand well – active immune suppression mediated by the highly adaptable tumor for its survival. Prophage is a personalized cancer vaccine based on patient-specific antigens isolated from each patient’s tumor, bound to heat shock proteins to drive the activation of anti-cancer T-lymphocytes. The company has been exploring the use of Prophage in patients with Glioblastoma Multiforme (GBM), influenced in part by the decision of the NCI to fund the ongoing Phase 2 trial. Over the years the company had conducted Phase 3 trials in melanoma, renal cell carcinoma, and earlier phase trials in multiple other cancers. AGEN is no longer advancing Prophage programs in these tumor types however they are participating in an investigator-sponsored clinical study of Prophage plus the checkpoint inhibitor Yervoy (the anti-CTLA-4 antibody ipilimumab from Bristol-Myers Squibb) in patients with advanced melanoma. Additional work could be done with their internal checkpoint modulator pipeline in the future. It is certainly true to say (although harder to predict) that positive results from the GBM trial would transform the company. I suspect that a failure here would lead the company to drop the platform.

It’s important not to confuse the Prophage tumor vaccine effort with the QS-21 Stimulon adjuvant programs. This is the adjuvant that GSK has licensed for use in much of their vaccine work. GSK’s MAGE-A3 vaccine failure is one of the few settings in which QS-21 was used as a tumor vaccine adjuvant. The company expects approvals for use in a malaria vaccine this year, with 20 advanced trials underway at GSK and J&J. GSK’s renewed emphasis on its prophylactic vaccine business might help AGEN even more going forward.  AGEN receives a milestone payment when the first QS-21 containing vaccine is registered by GSK and also royalties on both prophylactic and therapeutic vaccines.

If AGEN seems difficult to get one’s arms around, it may be because of this three-platform business model. On the other hand, these three platforms address three critical components of immune modulation, with immunotherapy programs a few years away from the clinic, a very long-standing vaccine effort, and an adjuvant program that is not well appreciated outside the company. Valuing this collection of technologies has been difficult, and certainly progress in any or all three will be important catalysts going forward.

Dr Armen and Dr Stein are well aware of the fuzzy picture that the outside world, and investors in particular I suppose, have had of the company. The refocus on immune checkpoint modulators was very well received allowing AGEN to raise $56M from  investors in February.  AGEN has articulated specific goals to drive the company forward:

  • Execute on the 4-Ab programs internally and through partnerships. This includes IND filings for two or more programs within 2 years, developing appropriate strategic partnerships, and further advancing other checkpoint inhibitors that were acquired with 4-Ab, but have not been disclosed.
  • Leverage the value of the 4-Ab platform, as has just been done in the Merck deal
  • Reboot the Prophage program via combination use with immune checkpoint modulators as results warrant. One cautionary note – this will require additional translational research efforts that are just now getting underway.
  • Design personalized therapeutic interventions utilizing the vaccine platform and an understanding of the basis for immune suppression in individual patients. AGEN leadership envisions that this will be done by a combination of internal efforts and through strategic partnerships with centers of excellence in translation medicine.
  • Acquire a later stage asset in the immune-oncology space that would complement the evolving immunotherapy portfolio. That could be a good use of capital.

It’s a full dance card. We’ll keep an eye on AGEN as they execute on these critical goals, especially in the immunotherapy space.

Disclosure: I own no stock in AGEN and have no opinion as to the value of the stock or its’ future performance.