Immunotherapy for Cancer A Look Back and A Look Ahead

By Marc Voigt

When the history of cancer immunotherapy is discussed, what most often comes to mind are the remarkable achievements of the last decade. Cancer immunotherapy, or immuno-oncology (IO), is generally deemed to have started in 2011, when ipilimumab, an immune checkpoint inhibitor (ICI), received regulatory approval. This event signaled the start of a revolution in cancer therapeutics to find functional cures through the power of patients’ own immune systems, instead of relying on foreign, toxic substances such as chemotherapeutics.

The approval of ipilimumab was soon followed by the approvals of pembrolizumab and nivolumab in 2014. Whereas ipilimumab inhibits an immune checkpoint called CTLA-4, pembrolizumab and nivolumab both inhibit an immune checkpoint called PD-1.

In the first wave of IO, ICIs were deployed as monotherapies, and they showed what leveraging the immune system’s power could achieve. By blocking a single immune checkpoint used by cancer to hide from and evade cytotoxic T cells, an ICI could eradicate entire tumors through the natural, preexisting T-cell infiltrate.

Unfortunately, even though ICIs have shown substantial potential, most patients do not respond to ICI monotherapies, and therefore the clinical success of ICI monotherapies is limited to a small portion of the population across various solid tumor indications.

When the long-sought goal of safely providing functional, lasting treatments for advanced cancer is finally achieved, an extra measure of recognition may be accorded to the first IO-IO combination therapies. In late 2015, nivolumab and ipilimumab became the first IO-IO combination to receive regulatory approval. In early 2022, nivolumab and relatlimab (an immune checkpoint inhibitor of lymphocyte activation gene-3, or LAG-3) became the second IO-IO combination to receive regulatory approval. For both combination therapies, the indication was metastatic melanoma.

This second wave of IO-IO approvals furthered clinical responses for patients, broadened immunotherapy’s reach against cancer (without chemotherapy), and reinforced the idea that combination approaches could, by tapping into multiple facets of the immune system, help attain the ultimate goal of curing cancer.

The scientists behind CTLA-4, PD-1, and LAG-3

So far, three immune checkpoints—CTLA-4, PD-1, and LAG-3—have been targeted by ICIs that have received regulatory approval. The work behind LAG-3 has been gaining attention ever since the anti-LAG-3 therapy relatlimab gained regulatory approval in 2022.

In 2018, James P. Allison, PhD, of the MD Anderson Cancer Center, and Tasuku Honjo, MD, PhD, of Kyoto University, were jointly awarded the Nobel Prize in Physiology or Medicine for their pioneering efforts with CTLA-4 and PD-1, respectively, and “discovery of cancer therapy by inhibition of negative immune regulation.”

According to a statement issued by the Nobel Assembly, “James P. Allison studied a known protein that functions as a brake on the immune system. He realized the potential of releasing the brake and thereby unleashing our immune cells to attack tumors.” … In parallel, Tasuku Honjo “discovered a protein on immune cells and, after careful exploration of its function, eventually revealed that it also operates as a brake, but with a different mechanism of action.” Allison obtained results as early as 1994 showing that inhibiting CTLA-4 was a promising anticancer strategy. Honjo’s work on PD-1 dates as far back as 1992.

With respect to LAG-3, this protein was discovered by Frédéric Triebel, MD, PhD, in the late 1980s. At the time, he was at the Institut Gustave Roussy, working on a project cloning mRNA that was expressed in activated T cells but not in resting T cells. After Triebel found that LAG-3 binds to MHC class II proteins—which play a vital role in the immune response—he saw a potential path to valuable therapeutics for patients and launched Immutep.

Unique nature of the newest approved immune checkpoint

LAG-3 is unique among the three approved immune checkpoints in that both its inhibition on T cells and its activation of antigen-presenting cells (APCs) stimulate the immune system against cancer, yet in completely different ways. This has allowed Triebel to pioneer multiple immunotherapies against cancer, as well as autoimmune diseases, with four pioneering candidates—three of which are in the clinic today, and one of which is at the preclinical stage. The preclinical candidate is the world’s first agonist to LAG-3 designed to tackle the root causes of autoimmune disease.

In oncology, the foundational work for antagonist LAG-3 antibodies began in Triebel’s laboratory over three decades ago with 17B4, an antibody that binds to LAG-3 on T cells and thereby blocks the interaction between LAG-3 and MHC class II proteins on APCs. Subsequently, Immutep, in partnership with CoStim Pharmaceuticals, developed another antagonist antibody that led to LAG525 (ieramilimab), an anti-LAG-3 blocking antibody. LAG525 is fully outlicensed to and under development by Novartis, which acquired CoStim in 2014.

However, the focus in oncology today for Triebel and his team at Immutep centers on the company’s first-in-class soluble LAG-3 immunotherapy. It is called efti-
lagimod alpha (efti), and it targets and binds to MHC Class II proteins on APCs (such as dendritic cells and monocytes). This novel MHC class II agonist takes an approach that is vastly different from the antagonist antibody approaches for blocking CTLA-4, PD-1, and LAG-3 checkpoints on T cells.

In simple terms, this soluble LAG-3 protein acts as a key to unlock a broad immune response against cancer. Through its high affinity for a subset of MHC II molecules on dendritic cells and monocytes, efti binds to and activates these APCs, leading to activation/proliferation of CD8⁺ cytotoxic T cells, CD4⁺ helper T cells, dendritic cells, natural killer cells, and monocytes. It also upregulates the expression of CXCL-10 and IFN-g, further boosting the immune system’s ability to fight solid tumors.

This comprehensive immune response, triggered in part by efti’s ability to engage dendritic cells—the “generals” of the immune system’s army—has many synergistic attributes with other therapeutics and offers significant potential to safely improve clinical responses for patients.

The future looks promising for this innovative immune stimulator. It has shown encouraging results in clinical trials with anti-PD-1 therapy, anti-PD-L1 therapy, chemotherapy, and in a triple combination therapy with standard-of-care anti-PD-1 therapy and chemotherapy.

In an all-comer PD-L1 Phase II trial called TACTI-002 (Two ACTive Immunotherapies), efti with pembrolizumab has doubled the overall response rates of this anti-PD-1 as a monotherapy in first-line non-small cell lung cancer (NSCLC) and in second-line head and neck squamous cell carcinoma (HNSCC). The compelling results and favorable safety profile led to oral presentations at the annual meetings of the American Society of Clinical Oncology and the Society for Immunotherapy of Cancer in 2022, and to fast-track designations in both first-line NSCLC and first-line HNSCC.

Efti has also shown positive efficacy with an anti-PD-L1 (avelumab) in patients with negative/low PD-L1 expression and IO-insensitive indications, as well as with standard-of-care chemotherapy in metastatic breast cancer. Its ability to safely improve clinical outcomes for PD-L1-negative, low-PD-L1-expressing, and high-PD-L1-expressing patients in combination with anti-PD(L)1 therapies may greatly expand the addressable patient population for chemotherapy-free IO-IO solutions.

As the industry strives to enable more efficacious therapies for cancer patients, the current clinical trial landscape in oncology offers clear evidence that combination approaches represent the future. In immuno-oncology, most ICI trials are in combination with other therapeutics, and there is a growing confluence of approaches to engage both adaptive and innate immunity and to maximize the potential of the immune response to eradicate solid tumors.

IO-IO combinations without chemotherapy hold the promise of increased efficacy and durability by safely tapping into the inherent power within our immune systems to effectively kill cancer. We expect the trend of promising clinical results from IO combination therapies to continue as we look to 2023 and beyond.

Marc Voigt is executive director, CEO at Immutep.

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