Dual-Pronged Immunotherapy Offers Hope for Tumor in Clinical Trials

In the realm of cancer treatment, immunotherapy has emerged as a groundbreaking approach over the past decade, leveraging the body’s immune system to combat malignancies. However, the efficacy of T cell-based immunotherapy varies across different cancer types, posing a challenge for oncologists and patients.

Researchers at the University of Pennsylvania are pioneering a novel strategy to tackle a recalcitrant form of pancreatic cancer that defies conventional immunotherapies. Their experimental approach involves activating myeloid cells through a combination of two treatments, showcasing promising results in animal-model studies and early human clinical trials. 

T cell-based immunotherapy has been a formidable weapon against various cancers, harnessing the power of activated T cells to target and eliminate malignant cells. Despite the success observed in some cases, there is a recognition that this approach may not be universally effective against all forms of cancer. This has prompted scientists to explore alternative strategies, leading to a focus on myeloid cells as potential agents in the fight against cancer. 

Myeloid cells, a diverse group of immune cells originating in the bone marrow, play a crucial role in anti-tumor immune responses. Unlike their lymphoid cell counterparts, myeloid cells possess the ability to be reprogrammed into an immunosuppressive state when infiltrating the tumor microenvironment. Recognizing this potential, researchers are investigating the activation of myeloid cells as an alternative avenue for immunotherapy. 

At the forefront of this research is a team of cancer biologists at the Perelman School of Medicine, University of Pennsylvania. Their focus is on simultaneously activating two myeloid cell receptors, CD40 and dectin-1, as a dual-pronged approach to tackle a resistant form of pancreatic cancer. The researchers hypothesize that this combination may overcome the limitations of conventional T cell-based immunotherapies. 

In their study published in Science Immunology, lead author Dr. Max M. Wattenberg and his team detailed their findings from mouse-model research. By targeting both CD40 and dectin-1 receptors, the researchers observed potent antitumor immunity. Notably, this approach proved effective in eradicating established tumors in mouse models of checkpoint inhibitor-resistant pancreatic cancer. 

The researchers highlighted that the combined targeting of CD40 and dectin-1 receptors activated myeloid cells in the tumor microenvironment. This activation was achieved through systemic β-glucan therapy targeting dectin-1 and CD40 agonist antibody treatment. Unlike conventional T cell-based immunotherapy, this approach successfully activated anti-tumor T cell responses in previously resistant pancreatic tumors. 

Myeloid cells, including macrophages, are known for their plasticity, allowing them to adapt to different roles in the immune response. The researchers observed that the dectin-1/CD40 activation not only depended on T cells but also required interferon-gamma and intra-tumoral macrophages. Importantly, this antitumor activity was independent of classical T cell-mediated cytotoxicity and immune checkpoint pathways. 

The findings from this research define a previously undescribed immunotherapy paradigm. Co-activation of complementary myeloid signaling pathways—CD40 and dectin-1—generated robust antitumor immune responses against pancreatic tumors resistant to conventional immunotherapy. The researchers believe that this dual-pronged approach taps into the therapeutic vulnerability of the myeloid compartment, demonstrating its potential as a potent cancer-fighting strategy. 

Encouraged by the promising preclinical results, the researchers have initiated a clinical trial to study the combination immunotherapy treatment in patients with pancreatic ductal adenocarcinoma. This marks a crucial step in translating laboratory findings into potential therapeutic interventions for individuals facing this challenging and often resistant form of cancer. 

The convergence of immunotherapy and myeloid cell activation represents a significant advancement in the quest for effective cancer treatments. The research conducted at the University of Pennsylvania sheds light on a novel approach to combat pancreatic cancer, offering hope for patients with limited treatment options.

As science continues to unravel the complexities of the immune system’s interactions with tumors, the development of targeted and personalized immunotherapies holds promise for transforming the landscape of cancer treatment. The ongoing clinical trial will be a pivotal milestone in determining the translational potential of this innovative dual-pronged immunotherapeutic strategy. 

Journal Reference  

Max M. Wattenberg et al, Cancer immunotherapy via synergistic coactivation of myeloid receptors CD40 and Dectin-1, Science Immunology (2023). DOI: 10.1126/sciimmunol.adj5097.