Using the Accelerator and Brake to Treat Cancer

research commentary

Research Strategy: Frédéric Triebel Using the accelerator and brake to treat cancer

It is a rare privilege for scientists to witness the discovery side effects in a small percentage of patients (15%). to which they gave birth reach maturity in their lifetime. Today, the industry is looking to develop drugs Since my group at the Institut Gustave Roussy in France that interfere with other checkpoints, such as killer discovered the immune checkpoint receptor lymphocyte immunoglobulin like receptor (KIR), T cell immunoglobulin activation gene 3 (LAG-3) in 1990, I have witnessed and and mucin domain-3 (TIM-3) and the LAG-3 receptor. I played a part in the birth and growth of the entire industry believe it is the latter that has produced the most interest that came to be known as immuno-oncology. so far, as evidenced by the number of pharma companies The field has escalated only recently. From 1990 to 2002, with clinical stage LAG-3 programmes – such as Bristol- my group was the only one publishing on LAG-3. Now Myers Squibb Co, Novartis, Merck & Co Inc, Regeneron the field has expanded to target a variety of conditions, Pharmaceuticals Inc and Boehringer Ingelheim GmbH. but cancer is still the disease seeing the most attention. Indeed, LAG-3 like PD-1 is a marker for exhausted CD8 At the American Society of Clinical Oncology (ASCO) tumour infiltrating lymphocytes (TILs) that proliferate annual meeting in early June, it was clear that LAG-3 and accumulate at the tumour site, which is the source of based therapies are now a major contributing factor in the tumour antigens. development of cancer treatments. Since these TILs are chronically stimulated by the To date, many traditional oncology drugs and treatments same tumour peptide over and over again, they then have been both minimally effective and highly costly. express inhibitory receptors (i.e. checkpoints) leading to Conventional cytotoxic chemotherapy agents are limited the dampening of the anti-tumour CD8 response. In other because of their toxicity to normal tissues. New targeted words, the first steps of tumour immune-surveillance are agents focus on vital signalling pathways. However, operative in about half of the patients with a so-called “hot these pathways are often redundant and invariably lead tumour” (i.e. a tumour infiltrated by numerous activated to tumour cell escape mutants, tumour regrowth and T cells producing interferon-gamma, a Th1 marker), but the ultimately patient death. last step, the tumour cell killing effector phase, is inhibited by PD-1 and LAG-3. Focus on checkpoint inhibitors At ASCO 2017, BMS presented initial efficacy data from A considerable amount of research from both academia and one of its LAG-3 clinical trials. BMS’s anti-LAG-3 antibody industry is now focused on checkpoint inhibitors. Nature has been in clinical development for more than three years provides a highly effective, specific and sensitive targeting and is combined with an anti-PD-1 antibody (i.e. removal device for cancer cells – the immune system – which evolved of two brakes on CD8 T cells), and BMS launched five new to detect external, foreign and abnormal molecules. Many large clinical trials last year. This makes nine combinatory cancers produce mutant proteins that are recognisable as LAG-3 antibody clinical trials being run by BMS, involving foreign by the immune system. The ability of tumour cells nearly 3,500 patients. to engage checkpoint receptors expressed on immune cells Another ASCO 2017 highlight was the recent registration inhibits anti-tumour immunity. The use of checkpoint by the FDA of the first combination of an active inhibitors blocks tumour-mediated inhibitory signals. This immunotherapy with a standard of care chemotherapy. This enables the immune system to mount a more effective anti- has revealed a change of mind in the oncology field where tumour response. physicians have been reluctant for decades to combine an At first, the focus concentrated on blocking the cytotoxic immunostimulant together with a cytotoxic, potentially T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint. immunosuppressive, chemotherapy. Indeed, Merck’s Phase To date, there has been only one US Food and Drug 2 trial of 123 patients combining Keytruda with pemetrexed Administration-approved CTLA-4 checkpoint inhibitor – is the first ever active immunotherapy combined with the monoclonal antibody ipilimumab. This was authorised conventional chemotherapy in an advanced cancer (non- in 2011 for treating skin melanoma, but it can have small cell lung cancer) to be approved by the FDA. This serious side effects. Indeed, releasing the CTLA-4 brake on comes 20 years after the first approval in 1997 of passive activated T cells with ipilimumab makes the ones specific immunotherapies, with rituximab and trastuzumab being for tumour cells more cytotoxic, which is the desired effect, cytotoxic antibodies directed against tumour cells combined but it also makes the other T cells specific for self peptides with chemotherapies. These passive immunotherapies, expressed in normal organs (e.g. thyroid, colon, liver) subsequently including cetuximab, changed the face more aggressive, which leads to severe autoimmunity (i.e. of the industry early on by establishing themselves as thyroiditis, colitis, hepatitis) in about 30% of patients. antibody blockbusters. It’s still too early to say whether In part for this reason, programmed cell death ligand 1 a new checkpoint inhibitor like an anti-LAG-3 antibody (PD-L1) and its receptor PD-1 have been a focus of more will preferentially be used in the long term with an anti- recent activity. A number of drugs targeting PD-1 have PD-1 antibody as described above, or alternatively, with been approved by the FDA in recent years. These have a first-line chemotherapy, thus lowering the cost of drug better response rates (e.g. 30-35%), but still present serious treatment.

Also at ASCO 2017, we at Prima BioMed Ltd presented positive safety and efficacy data from the first part of our History of LAG-3 AIPAC Phase 2b clinical trial for our lead product IMP321 (LAG-3Ig) in metastatic breast cancer (MBC). AIPAC (Active Immunotherapy PAClitaxel) is Prima’s multicentre, Lymphocyte Activation Gene-3 (LAG-3) was first cloned Phase 2b, randomised, double-blind, placebo-controlled in 1988 through hybridisation subtraction as a mRNA study in hormone receptor-positive metastatic breast cancer expressed in human activated T cells, along with other patients receiving IMP321 or placebo as adjunctive to first- mRNAs coding for the LAG series (i.e. LAG-1, LAG-2 line weekly chemotherapy, paclitaxel. et al). Then, the genomic LAG-3 DNA was cloned and In addition to Keytruda, IMP321 represents one of the some structural similarities indicated that LAG-3 was first proposed active immunotherapy drugs in which the distantly related to CD4. Indeed, LAG-3 lies adjacent to patient’s own immune system is harnessed to respond to a burst of tumour antigenic debris created by a chemotherapy the gene for CD4 on human chromosome 12 (12p13) injection. As a first-in-class antigen presenting cell (APC) and shares the same ligands – MHC class II molecules. activator, IMP321 boosts the network of dendritic cells in However, while CD4 serves as a co-stimulatory receptor the body that can respond to tumour antigens for a better associated with the TCR/CD3 complex for a subset of anti-tumour CD8 T cell response. T cells, LAG-3 serves as a co-inhibitory receptor The data presented at ASCO 2017 by Prima BioMed expressed on both CD4 and CD8 T cells and is showed a very encouraging disease control rate for associated with an exhausted phenotype in tissue metastatic breast cancer at 87%. The run-in phase trialled (tumour or auto-immune disease lesions) infiltrating the safety, immune-monitoring and activity of 15 patients, and provided the recommended Phase 2 dose for the lymphocytes. These fundamental discoveries opened the ongoing randomised Phase 2b trial of 226 patients. way to differentiated therapeutic antibody approaches in It has now been demonstrated that IMP321 leads to both oncology and auto-immune diseases. In addition, a sustainable increase and activation, of more than six the soluble LAG-3 receptor itself (LAG-3Ig) can be used months, of APC and CD8 T cells, together with an improved as a MHC class II agonist to activate antigen presenting baseline Th1 status (i.e. a sustained serum interferon- cells, leading thereafter to a sustained increase of gamma increase). cytotoxic CD8 T cells producing interferon-gamma, a cell In addition, the primary pharmacodynamics, the subset known to be associated with tumour regression increase of APC numbers in the blood and activation, were consistent with the mechanism of action of IMP321, a in patients. first-in-class APC activator. This is essential, because in contrast to immune checkpoint inhibitors, the mechanism of action of IMP321 is not only restricted to T cells, but perspective as there is for instance a clear immunological has a broad effect on other immune subsets such as background in the early phases of development for most monocytes, dendritic cells or NK cells. The secondary of these diseases, even the ones not categorised as auto- pharmacodynamics, the demonstration of the increase in immune disorders such as arteriosclerosis and Alzheimer’s CD8 T cell numbers and baseline Th1 status, were very disease. Given the success of the immune checkpoint field in positive in the context of anti-tumour efficacy in patients. oncology, and the investment in this sector, there is almost Whilst I have witnessed the field reach maturity, we limitless mileage as to what the immunotherapy field have only begun to scratch the surface of the potential can achieve. of checkpoint molecules for drug development for cancer, and a variety of other autoimmune and neurodegenerative References: diseases. In contrast to the PD-1/PD-L1 interaction, 1. https://www.bloomberg.com/gadfly/articles/2017-05-11/merck- the 3D structure of LAG-3 and the amino acid residues keytruda-combination-approval-good-news-but-how-good interacting with its ligand, a monomorphic determinant 2. https://www.globaldata.com/store/report/gdhc057poa--immuno- on the MHC class II molecules DR, DP and DQ, are not oncology-strategic-insight-multi-indication-and-market-size- yet known. In addition, the transducing properties of the analysis LAG-3 cytoplasmic domain are yet to be understood. We need to know much more about how LAG-3 actually works. However, the steady increase in clinical trial results is increasing the excitement for the immuno-oncology field. Frédéric Triebel, MD, PhD, is a French immunologist Merck’s Keytruda alone is forecast by analysts to generate and currently chief scientific and medical officer of nearly $7 billion by 2020.1 The research and consulting firm Prima BioMed Ltd, following the company’s acquisition GlobalData forecasts the total immuno-oncology market to of Immutep SA, founded by Dr Triebel in 2001. This be worth more than $19 billion, and by 2024 this will have followed his discovery of the LAG-3 immune control risen to $34 billion.2 mechanism in 1990 and subsequent work in the Many of the chronic diseases that desperately need collaboration between Institut Gustave Roussy and treatments have major causal contributory factors, Merck Serono to establish LAG-3’s mechanism of including genetics and external or lifestyle influences. action in T cells and dendritic cells. However they can be approached from an immunological