Bristol Myers Squibb’s recent phase III success provided the first late-stage confirmation for a novel immune checkpoint target in nearly a decade. This could herald the next generation of checkpoint inhibitors against cancer.\n\n\n\nLast month, the antibody drug relatlimab, developed by Bristol Myers Squibb, increased the progression-free survival of melanoma patients in phase III. These promising results did more than support the efficacy of a single therapy. To many in the field, they validated the approach of targeting lymphocyte activation gene 3 (LAG-3) to treat cancer. \n\n\n\nWhile the world waits for a full dataset from BMS’s phase III trial, LAG-3’s proponents in European biotechs and elsewhere are already knee-deep in development of the next wave of immune checkpoint inhibitors, for LAG-3 and beyond.\n\n\n\nWhen immune T cells are exposed to cancer or chronic infections for too long, they sometimes become exhausted, losing their ability to fight the invaders. Immune checkpoints like PD-1 and LAG-3, which function as brakes on the immune system, contribute to this T cell exhaustion, says Frédéric Triebel, CSO and CMO at the LAG-3 specialist Immutep. Triebel spun out the Australian-European immunotherapy company in 2001 based on decades of pioneering research into LAG-3 at the Paris-based Institut Gustave Roussy.\n\n\n\nApproved first-generation immune checkpoint inhibitors block PD-1, PD-L1, and CTLA-4. These drugs have impressive long-term, durable responses as monotherapies – but only in about a quarter of patients, says Triebel. To reach a larger number of patients, companies are investigating ways to attack solid tumors via alternative immune checkpoint targets like LAG-3.\n\n\n\n\n\n\n\n\n\n\n\nImmutep designed a LAG-3 inhibitor that is being developed by Novartis in combination with its anti-PD-1 antibody spartalizumab in phase II trials for patients with melanoma and phase Ib trials for patients with triple negative breast cancer.\n\n\n\nSimultaneously inhibiting both PD-1 and LAG-3 – “releasing two brakes” -- has become the mainstream approach for many companies chasing LAG-3 as well, including BMS, Boehringer Ingelheim, MSD, and AstraZeneca, says Triebel.\n\n\n\nThe BMS phase III trial is a roadmap of sorts for LAG-3 approaches in development. Relatlimab binds to LAG-3 on exhausted T cells to restore their ability to fight cancer, and BMS tested it in combination with Opdivo, its blockbuster PD-1 immune checkpoint inhibitor. The company said the combination met its primary endpoint, which was improving progression-free survival for patients with untreated metastatic or unresectable melanoma, compared with Opdivo alone.\n\n\n\nThat combination of immune checkpoint inhibitors is key, says Eliot Forster, CEO of UK-based immuno-oncology company F-star. “What was clear even from BMS themselves is that inhibiting LAG-3 alone in an advanced cancer setting was not benefiting patients.”\n\n\n\nBecause LAG-3 inhibitors had failed in the past to demonstrate clinical efficacy as monotherapies, Forster adds, industry interest had waned compared to other immune checkpoints like TIGIT and other novel cancer immunotherapy targets like IDO. \n\n\n\n“There was an idea that we’d already mined through CTLA-4, PD-L1, and LAG-3, the checkpoint pathways that were available. Clearly, the BMS data turns all of that on its head,” said Forster.\n\n\n\nThe presence of LAG-3 in cancer cells is linked to poor outcomes for patients treated with traditional checkpoint inhibitors. In fact, LAG-3 is often present in patients that relapse after such therapies. “It’s becoming apparent that you need to remove that LAG-3 signal to get that durable effect,” Forster says. This has guided F-star to look at the patients who relapse after taking checkpoint inhibitors for its lead bispecific antibody, which targets both LAG-3 and PD-L1.\n\n\n\nNew advances in protein engineering are paving the way for bispecific molecules in the immuno-oncology space. Bispecifics can have the effect of a combination therapy, but hitting both targets with a single molecule can enhance the therapeutic effect. F-star’s lead drug is in a phase II trial in patients with head and neck cancers resistant to checkpoint inhibitors targeting PD-1.\n\n\n\nOther biotechs are pursuing bispecifics for the next generation of checkpoint inhibitors, particularly blocking a protein target called 4-1BB. For example, Genmab in Denmark has partnered with the German giant BioNTech to test dual 4-1BB/PD-L1 and 4-1BB/CD40 inhibitors in phase I clinical trials\n\n\n\nTriebel is less excited about a bispecific approach, especially for LAG-3. “It’s not obvious this is going to work,” he says, given the scant track record of approved bispecifics in oncology. Currently, Amgen’s Blincyto (blinatumomab) is the only approved bispecific for cancer therapy.\n\n\n\nDespite the excitement around BMS’s announcement, “this is still the early days of LAG-3,” says Eric Vivier, SVP and CSO of Marseille-based Innate Pharma. Disclosure of BMS’s full dataset in the coming months may help paint a more complete picture.\n\n\n\nInnate Pharma suffered a phase II failure of a checkpoint inhibitor in 2017, but is developing an alternative candidate called monalizumab in phase III testing with AstraZeneca for head and neck cancers, and in phase I for solid tumors. Vivier calls monalizumab a ‘broad-spectrum’ immune checkpoint inhibitor as it targets the checkpoint NKG2A, which is found on several types of immune cells.\n\n\n\nVivier thinks harnessing innate immunity through a broad-spectrum approach will be an important approach to the future of immunotherapies. “We are all waiting for a second wave,” he says. “Everyone is expecting it to break the plateau that we are facing with the first wave of immunotherapeutic agents.”\n\n\n\n\n\n\n\nThis article was updated on 29/04/2021 to correct the development stage of monalizumab to phase III.\n\n\n\n\n\n\n\nCover image from Elena Resko. Data figure from Jon Smith.