Advances in Activating the Immune System Against Cancer: Immunotherapies at ESMO 2024

Science and technology are making major advances in cancer treatment, enabling the development of more complex and effective therapies. Immunotherapies are considered the forefront of these innovative approaches. Studies presented at the 2024 ESMO Congress revealed striking new strategies for regulating the immune system against cancer. 

Cancer and the Immune System: A Complex Interaction

Cancer cells and the immune system interact through various pathways and cell types. To affect cancer cells, the immune system uses many molecules and signaling pathways. Targeting these molecules and signals can offer major benefits in cancer treatment. In this context, the E3 ligase Casitas B-lineage lymphoma proto-oncogene B (CBL-B) is a negative regulator of the immune system. HST-1011, a selective oral CBL-B inhibitor, was developed to activate immunity by suppressing CBL-B. The phase-one SOLAR1 study in 28 patients demonstrated clinical responses with this agent.

BioNTech’s Study Combining an mRNA Vaccine and CAR-T Cell Therapy

A phase I study conducted by BioNTech, the biotechnology company of Uğur Şahin and Özlem Türeci, is designated BNT211-01. It evaluates a combination of CLDN6 CAR-T cell therapy and an mRNA vaccine encoding CLDN6. These are being assessed together.

Targeting claudin 6 (CLDN6), CAR-T cell therapy has emerged as one of the most exciting recent developments in immunotherapy. CLDN6 is expressed at low levels in normal tissues but highly expressed in many cancers. This makes CLDN6 an ideal molecule for targeting cancer cells. CAR-T cell therapy developed against CLDN6 has the potential to launch a specific attack on cancer cells.

CAR-T cell therapy aims to genetically modify T cells from the patient’s own immune system so they can recognize cancer-specific targets and destroy these cells.

In the BioNTech study, CAR-T cell therapy targeting CLDN6 was combined with an mRNA vaccine encoding CLDN6, the CARVac vaccine. This RNA vaccine enables better recognition and continued stimulation of the CLDN6 target by T cells. The combination was developed to improve treatment effectiveness and produce a longer-lasting immune response.

By increasing the presentation of CLDN6 in the body, the RNA vaccine enables CAR-T cells to find and recognize the target more effectively. This may reduce the risk of cancer returning by producing a sustained immune response against cancer cells during treatment.

Studies presented at ESMO 2024 showed encouraging results with this combination. In a clinical study, CAR-T cell therapy targeting CLDN6 combined with an RNA vaccine produced an objective response in 38% of treated patients. This is considered an impressive result in cancer treatment. The therapy was particularly effective in patients with high CLDN6 expression.

New Targets: B7H7 and Other Immune Checkpoints

Another new molecule targeted in immunotherapy is an immune checkpoint known as B7H7. The antibody HBM1020, which targets B7H7, aims to increase T cells’ response against tumors. Early-phase studies reported favorable responses in some patients receiving this antibody.

The immune system consists of more than T cells; myeloid cells also play an important role. Molecules such as interleukin-1 receptor accessory protein (IL1RAP) are important influences on immunity. Nadunolimab, a monoclonal antibody targeting IL1RAP, was tested with pembrolizumab in patients with some solid tumors (arising from tissues or organs), showing a safe profile and early responses in some patients.

Natural killer (NK) cells also play an important role in fighting cancer. A newly identified immune checkpoint molecule, IGSF8, can suppress NK cell activity. In this context, GV20-0251, an antibody targeting IGSF8, was tested in heavily pretreated cancer patients and showed antitumor activity with manageable toxicity.

Increasing T Cell Activation: DGKζ Inhibitors

One strategy for increasing T cell activation involves diacylglycerol kinase (DGK)ζ inhibitors. The DGKζ inhibitor ASP1570 was tested in more than 40 patients in a phase I/II study, which found specific toxicities and favorable responses in some patients.

The Limits of Immunotherapy: Disappointing STING Agonists

Although we have a deep understanding of how immunotherapy activates the immune system, not every preclinical finding produces the same effects in patients. Two phase I dose-escalation studies presented at the ESMO Congress illustrate this. They reported that the STING agonists dazostinag and BI 1703880, alone or combined with the anti-PD-1 antibody ezabenlimab, did not show the expected effects. These findings raise new questions about immunotherapy responses and resistance mechanisms.

Alternative Approaches: Cancer Antigen-Specific Antibodies

Exciting results are also emerging beyond immunomodulation. IMA401, a cancer antigen-specific antibody used in patients with HLA-A*02:01- and MAGEA4/8-positive tumors, produced objective responses in 6 of 29 patients and favorable results in 5 of 17 patients with high MAGEA4/8 levels.

Cancer Treatment in the Future

These studies help us understand the targets and strategies on which future cancer treatment will be based. Immunotherapies and alternative approaches are driving revolutionary developments in oncology that appear likely to lead to major advances in cancer treatment. Physicians and patients need to understand what these new options mean and how they will be used.