The French Connection – Lirilumab Edition

Bristol-Myers Squibb (BMS) has quietly changed the protocol of clinical trial NCT01592370. This Phase 1 clinical trial has evolved from a nivolumab (anti-PD-1) study in hematological malignancies (5/4/14) to include ipilimumab (anti-CTLA4) with nivolumab (4/8/14) to now include nivolumab, ipilimumab and lirilumab (anti-KIR) as of 10/30/14. The changes were noted on Twitter (where else?) by several biotech experts who posted this screen shot:

The striking thing to notice is the addition of lirilumab across the board.
The clinical trial includes the following indications/inclusion criteria:

Subjects must have histological confirmation of relapsed or refractory hematologic malignancy
Subjects with non-Hodgkin’s lymphoma or Hodgkin lymphoma must have at least one measureable lesion >1.5 cm as defined by lymphoma response criteria. Tumor sites that are considered measureable must not have received prior radiation therapy
Subjects with Multiple Myeloma (MM) must have detectable disease as measured by presence of monoclonal immunoglobulin protein in a serum electrophoresis: IgG, IgA, IgM,(M-protein ≥0.5 g/dl or serum IgD M-protein ≥0.05 g/dl) or serum free-light chain or 24 hour urine with free light chain. Excluded are subjects with only plasmacytomas, plasma cell leukemia, or non-secretory myeloma
Subjects with Chronic myelogenous leukemia (CML) must have evidence of the Philadelphia chromosome by polymerase chain reaction (PCR) or chromosome analysis
Life expectancy of at least 3 months
For subjects with lymphoma, either an archived Formalin fixed tissue block, or 7 to 15 slides of tumor sample for performance of correlative studies
Subjects must have received at least one prior chemotherapy regimen. Subjects must be off therapy for at least 3 weeks (2 weeks for oral agents) prior to Day 1

The trial covers Non-Hodgkin Lymphomas (NHL), Hodgkin Lymphoma (HL), Multiple Myeloma (MM), Acute Myelogenous Leukemia (AML), a subset of Chronic Myelogenous Leukemia (CML) and other hematologic malignancies. The requirement for biopsy tissue is to support biomarker analyses.
Lirilumab is an antibody developed by Innate Pharma …

Immuno-oncology (IO) combination therapy- why the angst?

Thoughts triggered by discussions over the last month or two, perceived sentiment on social media, reaction to clinical updates, and pre-AACR butterflies.
In 2015 Gordon Freeman of the Dana Farber Cancer Institute, one of the discoverers of the PD-1/PD-L1 axis, rang me up and asked if I would help write a review with he and Kathleen Mahoney, an oncologist doing a research rotation in his lab. We ambitiously laid out the argument that PD-1/PD-L1 directed therapeutics would be the backbone of important combination therapies and reviewed the classes of potential combinatorial checkpoints (http://www.nature.com/nrd/journal/v14/n8/full/nrd4591.html). We covered new immune checkpoint pathways within the Ig superfamily, T cell stimulatory receptors in the TNF receptor superfamily, stimulatory and inhibitory receptors on NK cells and macrophages, targets in the tumor microenvironment (TME), and so on. Importantly we also stopped to consider combinations with “traditional” cancer treatments, e.g. chemotherapy and radiation therapy, and also with “molecular” therapeutics, those directed to critical proteins that make cells cancerous. Regardless, it’s fair to say that we believed that pairing an anti-PD-1 mAb or an anti-PD-L1 mAb with another immuno-modulatory therapeutic would quickly yield impressive clinical results. A massive segment of the IO ecosystem (investors, oncologists, biopharma) shared this belief, and largely still does. Those stakeholders are betting clinical and R&D resources plus huge amounts of money on the promise of IO combinations. After all, the first IO combination of anti-CTLA4 mAb ipilimumab and anti-PD-1 mAb nivolumab has dramatically improved clinical response in advanced melanoma patients and to a lesser extent in advanced lung cancer patients. The downside is additive toxicity, and so the palpable feeling has been that new IO combinations would give a similar efficacy bump, perhaps even with less toxicity.
It’s now about two and a half years since we began drafting that paper and the inevitable letdown has …

The Big Tent: Halozyme is Targeting the Tumor Microenvironment, part 3 of an occasional series.

Many drug development programs claim to be truly unique and novel. It’s a mixed message really – complete novelty implies (or ensures) a high level of risk. It’s a bit difficult to attract early investment to such programs and maintain investor interest going forward. When we work with companies raising money, or are raising money ourselves, we are constantly trying to minimize risks, plural, as risks represent diverse aspects of a program or company: technology risk, biology risk, clinical risk, commercial risk, to highlight just a few. Companies that can move novel programs forward while derisking them in multiple areas certainly warrant our attention – for the scientific thesis and the investment thesis. We recently wrote about Innate Pharma, a company with first-in-class programs targeting NK cell immune checkpoint pathways (link 1). This is a good example of a company that has shed biology and clinical risks as the partnership with Bristol-Myers Squibb (BMS) continues to grow. The entire second tier of antibody-drug conjugate linker/payload companies (Redwood, Igenica, Mersana, Catalent and many others) will remain technology risk-heavy until each individual company either secures partnerships that eventually move ADCs into the clinic, or get their themselves. We could go on and on.
A few weeks ago I asked for companies and programs targeting the tumor microenvironment. Among the responses I got these:

Halozyme (Nasdaq: HALO) has a lead program that is very novel and I think scientifically is very interesting and has understood biological risk. We’ll talk about other risk elements in a bit, but science first. PEGPH20 is a pegylated version of the company’s approved recombinant human hyaluronidase (rHuPH20; brand name Hylenex). Hylenex is licensed to several partners, and provides a steady income stream from royalties. Hyaluronidase catalyzes the random hydrolysis of 1,4-linkages between 2-acetamido-2-deoxy-b-D-glucose and D-glucose residues in hyaluronan (HA), a constituent …

The Tumor Microenvironment – A Big Tent

 We have talked repeatedly about the promise of immuno-oncology, and with good reason. Very recent data show that the landscape of cancer care is changing rapidly and dramatically for the better. We continue to see contributions from diverse therapeutic modalities: immune checkpoint modulation, novel antibodies, bispecifics, CAR T therapy, TCR therapy and others. Massive amounts of resources have poured into this space, and interesting new companies continue to launch in the Boston area: Surface, Unum, Potenza, Enumeral to name just a few.

The last decade has seen intense focus on the immune checkpoint field, and clinical development in that space is encompassing combination therapy as the defining principal to advance treatment (Mahoney et al. NRDD, submitted). While much of the effort is driven toward combining antagonists of T cell immune checkpoints (CTLA4, PD-1, TIM-3, etc) with T cell activators (4-1BB. OX40, CD27, etc), this approach may be self limiting due to the toxicity associated with hyper-activation of T cells (cf. CAR Ts and BiTES) alongside the limitation of targeting just one arm of the immunosuppressive armature deployed by tumors.

Further, we understand that affecting outright cures in more patients is a dramatic step change, and we are not there quite yet, outside of hematology perhaps. It is obvious (we think) that curing cancer will require taking down the infrastructure that supports tumor cell survival, proliferation, resistance and metastasis. For solid tumors and niche-homing leukemias/lymphomas this infrastructure is built on the foundation of tumor cell/stroma interaction, where we define the stroma as extracellular matrix and associated cells – tumor associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), tumor associated fibroblasts, endothelium, other mesenchymal-lineage cells, etc. The composition may vary from indication to indication, with more or less complexity.

Let’s set the stage using three biology buckets:
 

Immuno-oncology focuses intently on tumor cells and tumor-expressed antigens, and …

Immune Checkpoint Therapeutics – Part 3: a) Innate immunity targets and b) IDO

Lets quickly set the stage. In part 1 we reviewed the CTLA4 and PD-1 pathways and therapeutics targeting these pathways. In part 2 we brought in a few more targets within the immunoglobulin superfamily: LAG-3, TIM-3, B7-H3, B7-H4, and very briefly TIGIT and VISTA. Then we reviewed therapeutics being developed to target proteins in the TNF receptor (OX40, CD40, 4-1BB, CD27, GITR) and ligand (CD70) superfamilies.
 While some of these pathways play a role in the innate immune system, they are all more closely aligned with the adaptive immune system. The innate immune system is hard-wired, triggering a rapid immune response, while the adaptive immune system relies on the orchestrated interaction of antigen presenting cells (dendritic cells, macrophages, etc) with T cells and B cells, leading to a robust immune response and, importantly, immunologic memory, i.e. memory of “that which” induced the immune response in the first place. Memory underlies immunity, as in “I am immune to…”, and is the basis for vaccination. In the context of oncology, memory allows sustained immune response to cancer cells over time.
In most immune responses to pathogens, both the innate and adaptive arms of the immune system are critical for efficient and sustained protection. We are learning from work with innate immune checkpoint therapeutics that the same may hold true for anti-tumor immunity.
One of the critical cells in the innate immune response is the natural killer (NK) cell. The name tells their story, as these cells are primed to disgorge toxins onto pathogens and pathogen-infected cells or tissue. Recently, an adaptive immune role for NK cells has been described, a finding that only increases the importance of this cell type. The activity of NK cells is controlled to a great degree by the killer inhibitory receptors.
Killer inhibitory receptors come in 2 flavors: killer cell immunoglobulin-like …

AML Therapeutics Part 3: Immunotherapy

Ryan Teague and Justine Kline recently put together a nice review of immune evasion in acute myeloid leukemia (AML). The open access paper is available online (http://www.ncbi.nlm.nih.gov/pubmed/24353898). These authors have particular interest in tumor escape from immune surveillance by two interesting mechanisms. The first is termed T cell exhaustion, and refers to a non-responsive state induced in CD8+ (cytotoxic) T cells. The second is immune suppression, mediated by TGFbeta and regulatory T cells (Tregs). Other means used by tumor cells to avoid the immune system include deactivation by co-opting signals that directly shut down immune responses, such as PD-1 and other signaling mechanisms.
Why the interest in immunotherapy for such an aggressive cancer? There are a number of good reasons. First I think it is fair to state that targeted therapeutics (small molecule drugs) and antibodies (mAbs, ADCs, bispecifics) have yet to achieve a breakthrough in AML. The best of these drugs, even in combination, are only modestly effective. The second reason, implicitly recognized by the T cell engaging bispecific antibodies (BiTEs, DARTs) and by the still nascent CAR-T cell engineering technology, is that there is evidence to suggest that AML can be controlled by an effective immune response. This evidence comes from the leukemia transplantation field. As Teague and Kline state:
“Treatment with modern chemotherapy regimens often induces complete remission, but a majority of patients will ultimately relapse … it has been recognized that allogeneic stem cell transplantation can be curative for some patients with AML … derived from the so-called graft-versus-leukemia effect thought to result … Unfortunately, only a minority of patients with AML are candidates for this procedure.”
Those who are familiar with allogeneic SCT will further recognize that this is a risky procedure that can outright fail. So, are there safer or more direct ways to harness an anti-tumor …