In the evolving field of oncology, one of the most powerful emerging strategies combines two groundbreaking modalities: induced pluripotent stem cell (iPSC)-derived immune cells and Immune Cell Engagers (ICEs). Together, they represent a new frontier in cancer treatment - uniting precision, persistence, and flexibility to overcome the resistance mechanisms that limit current immunotherapies particularly in the context of solid tumors.

Traditional immunotherapies - such as checkpoint inhibitors or T-cell engagers - have transformed cancer care but face limitations when it comes to resistant tumor types, immunosuppressive microenvironments, and advanced disease stages with heavily pre-treated patients. By combining engineered iPSC-derived immune cells with next-generation ICEs, Evotec is addressing these challenges head-on through a dual mechanism of action.

ICEs are bispecific or multispecific biologics designed to redirect immune effector cells toward tumor cells. When paired with iPSC-derived immune cells - such as iNK, iαβT, iγδT cells, or iMACs - these engagers can amplify anti-tumor responses by harnessing both the body’s endogenous immune system and the therapeutic iPSC-derived cells.

This combination approach results in superior tumor cell killing compared to ICE monotherapy. ICEs act as molecular bridges, connecting immune cells to their targets while simultaneously triggering immune cells activation towards tumor cell killing. The presence of fully functional engineered iPSC-derived cells enhances this response, providing a robust and renewable source of effector cells with consistent potency.

One of the key challenges in oncology is tumor resistance - arising from immune suppression, stromal barriers, or immune desert phenotypes. Evotec’s strategy directly addresses these hurdles by engaging multiple immune pathways simultaneously.

• Immune suppression is counteracted through persistent activation of iPSC-derived immune cells that remain functional even in inhibitory environments. Genetic engineering strategies of iPSC-derived immune cells as the knockout of inhibitory checkpoints combined with ICEs can overcome tumor-driven exhaustion mechanisms.
• Tumor microenvironment (TME) barriers are bypassed by ICEs that can redirect cells to otherwise inaccessible tumor sites.
• Immune desert tumors, often resistant to checkpoint blockade, can be targeted through engineered immune cells equipped with enhanced cytotoxic machinery.

Together, these mechanisms create a more comprehensive and adaptable response against diverse tumor landscapes.

A major advantage of this combined approach is adaptability. ICEs can be engineered to recognize multiple tumor antigens or immune checkpoints, allowing for dynamic modulation of immune responses. This means therapeutic strategies can evolve alongside the tumor’s biology, maintaining efficacy even as cancer cells adapt.

Importantly, this flexibility reduces the need for extensive genetic engineering of iPSC-derived cells. Instead, the modular design of ICEs provides a fast, scalable, and customizable way to redirect therapeutic cells toward new or resistant targets.

Evotec’s approach integrates biomarker-informed patient selection to optimize outcomes. By identifying molecular signatures that predict responsiveness to ICEs or specific iPSC-derived cell types, Evotec aims to tailor treatments for the patients most likely to benefit.

This precision-driven model reflects a broader shift in oncology - from one-size-fits-all therapies toward personalized cancer immunotherapy. Combining advanced analytics, cell biology, and biologics discovery, Evotec’s platform supports the rational design of synergistic treatment combinations.

Central to Evotec’s strategy is its proprietary Mytomab platform, a next-generation family of ICEs that enhance antibody-dependent cellular cytotoxicity (ADCC) and boost natural killer (NK) cell engagement.

Preclinical data have demonstrated that Mytomab can redirect iNK cells against HER2-positive solid tumors via CD2 and CD16 interactions, significantly amplifying their killing potential. In head-to-head comparisons, the combination of iNK + Mytomab achieved superior tumor cell clearance compared to iNK cells alone.

This synergy extends to other immune cell types as well. For example, loading iγδT-cells with a CD3 engager has been shown to markedly increase their tumor cell killing capacity. The mechanism involves enhanced downstream TCR signaling, resulting in stronger and more sustained cytotoxic responses.

A critical benefit of Evotec’s iPSC-based technology is its scalability and manufacturing flexibility. Unlike autologous cell therapies that require patient-specific manufacturing, iPSC-derived immune cells can be produced off-the-shelf at scale, enabling broader patient access and faster delivery.

This manufacturing advantage extends to combination therapies, where both ICEs and iPSC-derived cells can be administered as standardized products. The result is a more consistent, cost-effective, and clinically adaptable therapeutic platform that can be deployed across multiple indications and disease stages.

Evotec’s integrated iPSC and ICE platforms are already advancing through multiple discovery and preclinical programs. The company has successfully generated:

• Four distinct immune cell types derived from iPSC (iNK, iαβT, iγδT, iMACs)
• Four active projects in the Mytomab pipeline
• Proof-of-concept (PoC) studies demonstrating synergistic activity between iPSC-derived cells and ICEs

These milestones highlight Evotec’s position as a leader in the development of rationally designed immuno-oncology strategies, capable of addressing resistance and improving patient outcomes across solid and hematologic malignancies.

The convergence of cell therapy and biologic engagers represents a paradigm shift. It enables immune systems - both natural and engineered - to be precisely directed, persistently activated, and dynamically adapted to tumor evolution.

By leveraging its proprietary iPSC platform, next-generation ICE technologies, and deep expertise in biomarker-driven precision medicine, Evotec is pioneering a new generation of synergistic, off-the-shelf immunotherapies.

These innovations hold promise not only for improved clinical efficacy but also for scalability, manufacturing efficiency, and access - critical factors in bringing advanced therapies to a broader patient population.

Evotec continues to advance its immuno-oncology programs with a focus on rational combination design, functional proof-of-concept models, and translational strategies that move discoveries from bench to bedside.

For more information about Evotec’s iPSC-based immuno-oncology capabilities and combination therapy platforms, visit www.evotec.com or contact info@evotec.com.