LAG-3 Pioneer Frédéric Triebel Discusses Its Potential in Immunotherapy

Cancer Immunotherapy

For the immuno-oncology space, November means the Society for Immunotherapy of Cancer (SITC) Annual Meeting. This year, it brought together leaders from academia and industry, including Australian biotech company Immutep.

In the LAG-3 (Lymphocyte Activation Gene-3) field, before Bristol Myers Squibb and Merck & Co., there was Immutep, still the only pure-play LAG-3 company. LAG-3 is a cell surface molecule that plays a vital role in regulating the immune system. It was discovered in 1990 by Dr. Frédéric Triebel, M.D., Ph.D., Immutep’s chief scientific officer and chief medical officer.

LAG-3 is a priority focus in cancer immunotherapy because its inhibition can make PD-1 inhibitors like Merck’s Keytruda (pembrolizumab) and AstraZeneca's Imfinzi (durvalumab) work in more patients. LAG-3 regulates an inhibitory immune checkpoint pathway that limits the activity of T cells, impairing their ability to attack and destroy tumor cells. Developing a drug to counteract this could restore the effector function of exhausted T cells and lead to more remissions.  

In 2011, CTLA-4 was validated as an immune checkpoint, followed in 2014 and 2015 by PD-1. In March 2021, BMS presented the first Phase III data from a trial evaluating an anti-LAG-3 antibody, relatlimab. In combination with Opdivo, relatlimab met the primary endpoint of progression-free survival in first-line metastatic or unresectable melanoma. This, Immutep Executive Director and CEO Marc Voigt told BioSpace, validated LAG-3 as a checkpoint. It was a monumental step for the field, as relatlimab was the first anti-LAG-3 antibody to demonstrate a benefit for patients.

“They presented … the first results in terms of progression-free survival, which was very convincing, highly significant, and also, overall survival seems to be very strong,” Voigt said. In September, BMS announced that the U.S. Food and Drug Administration (FDA) had accepted for priority review of its Biologics License Application (BLA) for relatlimab in this indication. The FDA has set a target action date of March 19, 2022.

Immutep is looking to propel the LAG-3 wave begun by Triebel when he, along with colleagues, discovered the gene while working at the Institut Gustave Roussy (IGR), a large cancer center in Paris. The company recently presented data from two Phase II trials, involving its lead product candidate eftilagimod alpha (efti), a soluble LAG-3Ig fusion protein and antigen-presenting cell (APC) activator.

At SITC, Immutep presented the final overall survival (O.S.) data from the Phase IIb AIPAC study in HER2-negative/HR-positive metastatic breast cancer. In combination with paclitaxel chemotherapy, efti led to significant health benefits in patient majority subgroups, along with a statistically significant CD8 T-cell production increase. The median total survival benefit was 2.9 months in the efti plus chemotherapy arms compared with chemotherapy plus placebo alone. The highest O.S. of +19.6 months was found in the “low monocytes” group.

Immutep is also trialing efti in combination with Keytruda for non-small-cell lung carcinoma (NSCLC) and head and neck squamous cell carcinoma (HNSCC). Data presented at SITC from the Phase II TACTI-002 trial demonstrated an Objective Response Rate (ORR) of 29.7%, including 5 Complete Responses (C.R.s) in second-line HNSCC patients.

Given his primary role in developing the field of immuno-oncology, BioSpace asked Triebel for his thoughts on its current state.

“Fifteen years ago, we saw that we had to induce more T cells to get to cancer vaccines. Now we realize that very often, the natural preexisting T cell response is sufficiently important so that if you do a little trick, this could lead to long-term disease-free survival in some carcinomas,” he shared. 

Next, he said, “We have to find new pathways, inhibitory pathways, and LAG-3 is certainly an immune checkpoint now validated through Phase III.” He added that T cell immunoglobulin and ITIM domain (TIGIT) could one day be a validated checkpoint, despite its many failures during the past seven years.

Oncology is not the only therapeutic area that could benefit from LAG-3 intervention. On another arm of Immutep’s pipeline, the company is leveraging LAG-3 against autoimmune disease.

“You find LAG-3 expression only in a few sites in the body where you have chronic stimulation of T cells with the same antigenic peptide, whether it’s a tumor peptide or autoimmune peptide,” Triebel explained. After a few weeks, these T cells become exhausted due to this chronic restimulation and constitutively express LAG-3. “In autoimmune diseases, we use LAG-3 as a marker to target self-reactive exhausted effector T cells that accumulate at the autoimmune disease site. Then, we use LAG-3 as a functional receptor to increase negative signaling into these autoimmune T cells through a unique LAG-3 cross-linking mechanism with an agonist anti-LAG-3 antibody, IMP761. These self-reactive T cells, which are the root cause of autoimmunity, are then silenced.”

From a purely medical point of view, Triebel said this approach would seem to be more beneficial than general immunosuppressants like corticosteroids, methotrexate (often used to treat rheumatoid arthritis), or blockers of inflammation mediators. The challenge, he said, is, “you have to find the right epitope on LAG-3, organized by antibody, to make it work.”

According to Immutep, IMP761, an agonist antibody, is the only one of its kind currently in development. It is presently being studied at the preclinical stage and Immutep anticipates being in the clinic in approximately 18 months.

As for the future of immunotherapy, Triebel said, “I won’t say we should have more clinical trials, because there are about 2000 clinical trials. I would rather say that we should do the right ones, and maybe think a little bit more about combining approaches.” 

As far as combination approaches go, Immutep, whose portfolio includes both controlled and out-licensed programs, is in good company.

 “The reality is that these days, it’s not so much a race for monotherapies replacing one another, but it’s a race for combinations,” Voigt said. “They have to find the right way, and you need to do a lot more work - maybe boring work - l​ike scheduling and dealing with side effects … and we are very actively taking part in that.”

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