Immunotherapy is here to stay

Listen to this article on the DDW Podcast: DDW’s Megan Thomas spoke with Frédéric Triebel, the French immunologist/oncologist who is best known for his 1990 discovery of the LAG-3 immune control mechanism. Triebel shares insights from his career, expands on his experience with the company he founded, Immutep, and comments on the future of immuno-oncology (I-O). Background Lymphocyte-activation gene 3, or LAG-3, is a gene that provides the genetic information to make a cell surface molecule with biologic effects on T-cell function. Triebel reported the first cloning of the LAG-3 gene in 1990. Two years after this discovery, his team was able to show that the LAG-3 protein was a ligand for MHC Class II molecules like CD4. In 1997, the Triebel lab identified the LAG-3 amino-acid residues involved in LAG-3/MHC class II interaction. In 1998, Triebel et al. performed the first characterisation of the human CD4/LAG-3 gene locus, in the process identifying the LAG-3 promoter regulatory elements. Also in 1998, Triebel’s team were the first to characterise the negative regulatory role of LAG-3 on CD3/TCR signalling. In parallel, his team was the first to show that, as a soluble molecule, LAG-3 activates antigen-presenting cells through MHC class II signalling, resulting in antigen- specific T-cell responses. Triebel founded Immutep SA in 2001 to develop the clinical potential of LAG-3 and stayed with this company through to its acquisition by Prima BioMed in 2014. Prima BioMed rebranded as Immutep in 2017 and Triebel continues as Chief Scientific and Medical Officer of Immutep. Immutep, listed on ASX and NASDAQ, is a pure-play LAG-3 company, with five product candidates in development. Pipeline Immutep currently has three clinical, one pre-clinical, and one early- stage LAG-3 related product candidate under development. These include two antibodies for modulating immune responses in cancer and autoimmunity, which are being advanced through pharmaceutical partnerships with Novartis and GlaxoSmithKline. The company’s lead product candidate is eftilagimod alpha (efti or IMP321), a first-in-class antigen- presenting cell (APC) activator currently being investigated in clinical trials as a treatment (in combination with chemotherapy or anti-PD-(L)1 therapies) for various cancer indications. The drugs in development are as follows: Eftilagimod alpha (efti or IMP321) – immunotherapy for cancer IMP761 – pre-clinical immunotherapy for autoimmune disease LAG525 or leramilimab (IMP701) – immunotherapy for solid tumours, blood cancer and breast cancer (partnered with Novartis) GSK‘781 (IMP731) – immunotherapy in autoimmune diseases (partnered with GSK) Triebel has had many landmark moments across his long career as an immunologist, one of which was being the lead author on the paper in 1990, LAG-3, a novel lymphocyte activation gene closely related to CD4. The LAG-3 receptor was a new concept at the time. Triebel and his team knew that T cells to be activated need two signals, signal 1 through the T cell receptor and signal 2 through co-stimulatory molecules like CD4, CD8 or CD28. A few days following T cell activation, T cells return to a more quiescent state, and T cell deactivation is also an active mechanism mediated by co-inhibitory receptors such as CTLA-4, PD-1 and LAG-3. Looking back, looking forward I ask Triebel to look back on those early days and comment on what the future looked like at the time. Are we on track, ahead, behind today compared to what the team expected at the time? Triebel recalls thinking, “it’s now or never”. At the time, nobody was interested in LAG3, he says, so he committed to doing it himself through the founding of Immutep. This required convincing investors he was motivated enough, leaving the university, and building Immutep from the ground up. This period was difficult, with challenges such as the war in Iraq, as well as the fact that there was no real private money in France for a biotech venture such as this. He says: “But, we did raise a few million, and we started going into the clinic not with a blocking antibody but with a very different, more innovative concept, which is a soluble LAG-3 protein, which is now eftilagimod alpha, as an immunostimulant. So, in 2005, we were already in the clinic. It was, at the time, a very small dosing – a few micrograms combined with an antigen, in other words, an adjuvant to a therapeutic vaccine. So, the idea was to activate the dendritic cells locally to increase antigen presentations to the T cells. Indeed, this worked as we had seen increased activated T cell numbers in the blood. “The next step was to vastly increase the subcutaneous dosing to 30 mg efti in order to trigger the systemic activation of the dendritic cell network in the whole body. The first-in-man monotherapy trial studying our powerful antigen-presenting cell activator escalated efti dosing from 0.05mg to 30mg to treat advanced renal cell cancer, knowing that advanced cancer patients shed tumour antigens into the bloodstream continuously. We only treated patients for three months yet saw encouraging results and statistically significant increases in effector-memory CD8 T cells in all patients at higher efti dosing levels.” The breakthrough So what was the point at which the cancer immunotherapy breakthrough started to feel real? Triebel says that 30 years ago, they were working with renal carcinoma tumours from metastatic patients and realised that there were as many T cells at the tumour site as tumour cells. It really looked like auto-immunity driven by T cells. Then they realised that there were two or three immunodominant clonotypes, i.e., T cells with the same T-cell receptor. That means two or three T cells have multiplied enormously. And why did they do that? He says: “Because there are two or three immunodominant peptides derived for instance from tumour oncogenes, that leads to clonotypic T cell proliferation.” So, the concept of immuno-surveillance is working in patients with metastatic tumours, and this is good news to see these patients with a 'hot tumour' environment (i.e., many activated T cells at the tumour site), even though this natural immuno-surveillance was not enough to stop the tumour growth. He says: “Back then, everything was about cancer vaccines trying to induce more T cells specific for the tumour antigens but then in 2010, oncologists realised for the first time that by blocking the CTLA-4 coinhibitory receptor, you induce autoimmune disorders never seen before in oncology, as well as tumour regression in a fraction of the patients. Inducing de novo autoimmune disorders by strongly activated T cells, like thyroiditis, colitis, or pneumonitis in a few cancer patients, is indeed expected in the case of strong immunostimulation.” Around this time, the field of immunotherapy really broke through with the approvals of anti-CTLA-4 (ipilimumab) in 2011 and anti-PD-1 (pembrolizumab & nivolumab) in 2014. Then in 2015, nivolumab and ipilimumab became the first IO-IO combination to receive regulatory approval for melanoma. Triebel saw an opportunity to synergistically combine efti with these checkpoint inhibitors, given its markedly different mechanism of action. Efti would push the accelerator on the immune response by targeting antigen-presenting cells, while checkpoint inhibitors would release the brakes on the immune system by targeting T cells. The clinical results to date in melanoma, lung cancer, head and neck cancer have been encouraging. He says: “Our enduring belief that targeting two different cell subsets would be very effective in fighting cancer continues to strengthen as efti has increasingly shown its ability to safely improve clinical outcomes for patients in combination with anti-PD-(L)1 therapies.” Looking forward Triebel says that present I-O therapies is just the beginning of the story. He says: “We have treated the 'hot tumour' cancer patients, meaning the easy ones with a strong preexisting anti-tumour response at the tumour site. For patients with a lot of activated T cells producing interferon gamma at the tumour site, you'll just remove one break on the T cells, with an anti-PD-1 for instance, and that's enough for the T cells to eliminate a one kilo tumour mass disseminated at different anatomical sites. We have known for 50 years that T cells can do that – since the sixties. I mean, if you have Hashimoto’s disease, in three weeks your thyroid gland will disappear. The same for the pancreatic islets in the case of type one diabetes. So, we know that T cells can kill organs, so why not tumours? This is an immunologist’s view.” Looking forward, Triebel says that active immunotherapy is here to stay. With the success he has seen, he thinks that combining two I-O therapies in a chemo-free regimen for first-line or second-line treatment of metastatic cancers may help the majority of patients as long as one I-O is targeting dendritic cells like efti (to drive a broad immune response and an increase in activated T cells) and the other I-O is targeting T cells like anti-PD-(L)1 therapies (to remove the brake). DDW Volume 24 – Issue 2, Spring 2023 – Global Cancer Research Guide Biography: Frédéric Triebel, MD PhD, founded Immutep in 2001. He was appointed as Chief Medical Officer and Chief Scientific Officer following the acquisition of Immutep in December 2014 and joined Immutep's Board in 2022. Before starting Immutep, he was Professor in Immunology at Paris University. While working at Institut Gustave Roussy (IGR), a cancer centre in Paris, he discovered the LAG-3 gene in 1990 and in subsequent research identified the functions and medical usefulness of this molecule.