Addressing unmet challenges in macrophage cell therapeutic

Macrophages are paving the way for exciting new opportunities in cancer therapy - overcoming barriers faced by T-cell therapeutics in targeting solid tumors. Discover the exciting world of macrophage cell therapeutics, the importance of manufacturing, and how Evotec’s proprietary cell therapy development pipeline is helping to shape tomorrow’s therapies.

Cell therapies have emerged as one of the most promising immunotherapeutic strategies in the fight against cancer. In particular, chimeric antigen receptor T-cell (CAR-T) therapy has become notable for its strong efficacy in generating targeted antitumor responses in a broad range of hematological malignancies. CAR-T cell therapies have been approved by the United States Food and Drug Administration (FDA) to treat a number of hematological cancers, having been shown to dramatically improve the outcomes of patients with B-cell malignancies and Multiple Myeloma.

Despite the clinical success of CAR-T cells against some hematological cancers, CAR-T cell therapy has shown limited efficacy against solid tumors, which account for approximately 90% of all cancer cases. Several factors contribute to their diminished efficacy when combatting solid tumors: The tumor microenvironment (TME) has clever immunosuppressive defense mechanisms, while T-cells exhibit poor infiltration into the tumor. Furthermore, there is a lack of solid tumor antigen targets that provide adequate specificity and safety [1].

To overcome the challenges faced in treating solid tumors, novel macrophage-based immunotherapies are gaining attention. Macrophages can infiltrate tumors more easily and bring favorable immunomodulatory characteristics. Furthermore, their phenotypic plasticity allows them to be easily re-engineered to prompt antitumor activity. Several macrophage reprograming approaches have been developed, including the use of gene editing tools to inhibit immunosuppressive genes [2].

While macrophage-based cell therapies have garnered promising results in preliminary trials, the majority are based on autologous macrophages. Implementing an autologous cell therapy approach brings complications to macrophage therapeutic production: Patient material is limited and tricky to work with, while the cell manufacturing phase often requires personalized genomic profiling and gene editing, which is both costly and time-consuming.

Induced pluripotent stem cell (iPSC)-derived macrophages (iMACs) offer the opportunity to overcome the production bottleneck associated with autologous cell therapies. By opting for a reliable, scalable GMP manufacturing process, it’s possible to create allogenic macrophage cell therapy products with consistent high quality. Furthermore, iPSCs enable straightforward introduction of genetic material for gene editing-based cellular engineering.

In this article, we will highlight a promising iMAC approach for targeting solid tumors, and discover how opting for an iMAC cell therapy product can eliminate the need for combination therapies.

Overcoming the CD47 defense mechanism

CD47 is a protein highly expressed on the surface of all solid tumor cells, and represents a key component of the TME’s defense – acting as a ‘don't eat me’ signal for phagocytic cells. CD47 is a natural ligand for SIRPα, a membrane protein expressed on macrophages. When a macrophage approaches a tumor cell, CD47-SIRPα interactions prevent the macrophage from phagocytosing the tumor cell [3].

Several agents that disrupt CD47-SIRPα signaling have entered clinical trials in recent years. Many of these therapies consist of monoclonal antibodies or antagonist drugs targeting either CD47 or SIRPα. While these have yielded varying degrees of success, combination treatments of anti-CD47 or anti-SIRPα inhibitors with additional tumor targeting antibodies have often been required to produce significant anticancer efficacy [4]

To improve upon the efficacy of therapeutics targeting the CD47-SIRPα axis, a novel iMAC cell therapy approach holds promise of blocking this critical checkpoint with greater reliability. By gene editing iPSCs to knockout (KO) the gene coding for SIRPα, it’s possible to generate a highly potent iMAC cell therapy product resistant to phagocytosis inhibition by CD47-expressing tumor cells.

SIRPα knockout in iMACs improves phagocytosis of tumor cells

A recent study conducted by Evotec researchers investigated the activity of SIRPα KO iMACs manufactured via Evotec’s proprietary 3D iMAC differentiation process. Preliminary studies demonstrated that the SIRPα KO iMACs retain typical phenotype comparable to wild-type (WT) iMACs. Next, the researchers tested the phagocytic activity of SIRPα KO iMACs and WT iMACs against cultured Raji cells, a cell line commonly used as a preclinical tumor model that expresses CD47 and the tumor target CD20.

Raji cells were co-cultured for 20 hours with WT or SIRPα KO iMACs in the presence of different treatments (isotype controls, anti-CD20 antibody, anti-CD47 antibody or combined anti-CD20 + anti-CD47 (combo)). The tumor cell uptake by macrophages known as antibody-dependent cellular phagocytosis (ADCP) was then monitored by live-cell imaging via Incucyte (Figure 1).

Figure 1: Antibody-dependent cellular phagocytosis (ADCP) of RAJI cells by WT and SIRPα KO iMACs. Data expressed as mean ± SEM.

In the presence of anti-CD20 antibody for tumor targeting, SIRPα KO iMACs (represented by the dark blue graph line) showed augmented phagocytosis that was equivalent to WT iMACs treated with a combination of CD20- and CD47-targeting antibodies (black line). In addition to increased phagocytosis, the tumor-killing capacity of SIRPα KO iMACs loaded with anti-CD20 antibody was found to be comparable to WT iMACs in the presence of anti-CD47 antibody.

This finding has significant implications for iMAC-based anti-cancer cell therapy development. It demonstrates that the novel allogenic SIRPα KO iMAC cell product developed by Evotec overcomes the need for a treatment combination with anti-CD47 or anti-SIRPα checkpoint inhibitors, and has great potential to serve as the basis to develop innovative treatments for solid tumors.

Evotec’s scalable cell therapeutics platform

Good Manufacturing Practice (GMP) manufacturing ensures that cell therapies are produced in a consistent, controlled environment to meet stringent quality standards. This is crucial for cell therapies as it ensures product safety, efficacy, and reproducibility, laying the foundation for successful clinical outcomes and regulatory approval. Although the allogenic SIRPα KO iMAC cells used in the discussed phagocytosis study were of Research Use Only (RUO) grade, Evotec possesses in-house GMP manufacturing capabilities to generate GMP-grade iMAC cell therapy products.

The iMAC platform optimized for solid tumors is one of several iPSC-based cancer cell therapies developed by Evotec. Their growing portfolio includes natural killer cells (iNK), macrophages (iMACs) and αβ and γδ T cells (iT) (Figure 2). Each immune cell type can be leveraged to create multiple differentiated allogenic cell therapy products.

Figure 2: Evotec’s iPSC-based cell therapy pipeline for oncology

Evotec’s growing iPSC cancer cell therapy platform can be used as the basis to develop novel allogenic cell therapeutics without the complexities or production bottleneck associated with autologous therapies. Supported by Evotec’s world class GMP manufacturing facilities, the cell therapy platform is fully scalable, and empowers developers with reliable, highly pure, ready-edited cell therapy products.

The iPSC-based oncology cell therapy platforms represent a wider iPSC pipeline for cancer cell therapy and beyond. Evotec’s industry leading iPSC platform has been developed with the aim to industrialize the use of iPSC technology in terms of throughput, reproducibility and robustness for the development off-the-shelf allogeneic cell therapies. Starting with a GMP iPSC master cell bank, Evotec’s cell therapy manufacturing platform provides full scalability and wide versatility in the numerous cell types that can be generated. An integrated iPSC gene editing platform enables functional optimization of the individual cell therapy products, ensuring that they are optimally tailored for their intended therapeutic use. (Figure 3).

Figure 3: Schematic depiction of Evotec’s fully scalable GMP-compliant cell therapeutics manufacturing platform

A bright future ahead for cell therapeutics

Macrophage cell therapies hold much promise in combatting solid tumors with greater efficacy versus CAR-T cell therapies. Overcoming TME defense mechanisms like the CD47-SIRPα axis is key to optimizing macrophages to exhibit maximum antitumor behavior. iMACs derived from iPSCs offer distinct advantages over autologous macrophage therapies, enabling a consistent, scalable platform for clinical development.

Editing iMACs by knocking out SIRPα enhanced their phagocytosis activity against tumor cells. Evotec’s 3D iMAC differentiation platform facilitates the genetic engineering of iPSCs to create an innovative allogenic SIRPα KO iMAC cell therapy product against solid tumors. This is one of many exciting projects happening at Evotec, who are supporting the development of novel cell therapies based on various cell types.

Find out more about Evotec’s industry leading cell therapy platform

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References

1. Chen, K., Liu, M.L., Wang, J.C., Fang, S. CAR-macrophage versus CAR-T for solid tumors: The race between a rising star and a superstar. Biomol Biomed. Advanced online release. 2023. https://doi.org/10.17305/bb.2023.9675
2. Mishra, A. K., Banday, S., Bharadwaj, R., Ali, A., Rashid, R., et al. Macrophages as a Potential Immunotherapeutic Target in Solid Cancers. Vaccines. 2022;11(1), 55. https://doi.org/10.3390/vaccines11010055
3. Willingham, S. B., Volkmer, J. P., Gentles, A. J., Sahoo, D., Dalerba, P., et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. PNAS USA, 2012;109(17), 6662–6667. https://doi.org/10.1073/pnas.1121623109
4. Willingham, S. B., Volkmer, J. P., Gentles, A. J., Sahoo, D., Dalerba, P., et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. PNAS USA, 2012;109(17), 6662–6667. https://doi.org/10.1073/pnas.1121623109