The Future Of Cancer Drug Discovery Is Targeted Immune Activation
By Eric Poma, Ph.D., CEO, Calidi Biotherapeutics
Cancer drug discovery has changed considerably over the past two decades. Advances in genomics, immunology, and genetic engineering have given researchers a deeper understanding of the biological mechanisms driving cancer and created new opportunities to develop therapies around specific targets and pathways.
For many oncology therapies, particularly those intended to treat advanced or metastatic disease, success also depends on whether the therapy can reach tumors at sufficient concentrations and generate activity where it is needed without causing excessive systemic exposure. This has become important as oncology research moves toward more sophisticated immunotherapies and genetic medicines. The next phase of cancer drug discovery will require researchers to think about what a therapy does and where and how its therapeutic activity occurs.
Moving Beyond Broad Immune Activation
Immunotherapy has transformed cancer treatment by demonstrating that the immune system can be harnessed to recognize and attack cancer cells. However, many approaches depend on systemic immune activation, which can expose healthy tissues to therapeutic activity and contribute to inflammatory toxicities. These effects can limit dosing flexibility or patient eligibility.
Additionally, tumors have developed sophisticated mechanisms for evading immune destruction. The tumor microenvironment contains immune cells, stromal cells, blood vessels, and signaling molecules that interact with the tumor and can create conditions that suppress an effective anti-tumor immune response. This has made the tumor microenvironment a focus of oncology research.
Rather than activating the immune system broadly throughout the body, researchers are exploring strategies designed to concentrate immune activity within tumors. The goal is to deliver therapeutic agents directly into the tumor microenvironment, where they can potentially destroy cancer cells while also changing local conditions to support a stronger anti-tumor immune response. This shift toward localized immune activation could influence how the next generation of immunotherapies is designed.
Delivery Is Becoming Part Of Drug Design
Historically, drug discovery has often focused on identifying a biological target and developing a molecule capable of acting on it. In oncology, however, the ability to reach that target can be just as important as the therapeutic mechanism itself.
Tumors are highly heterogeneous. Differences in vascularization, immune composition, stromal barriers, and receptor expression can influence whether a therapy reaches the tumor in sufficient concentrations. The immune system can create another obstacle by recognizing and clearing biologic therapies from circulation before they reach their intended destination.
These challenges become even more pronounced in metastatic disease. Therapies administered directly into a tumor may be useful for accessible lesions, but treating cancer that has spread throughout the body requires approaches capable of reaching multiple distal tumor sites. As a result, delivery is becoming an integral part of therapeutic design rather than a challenge addressed later in development.
One area being explored is systemically delivered oncolytic virotherapy. Oncolytic viruses were initially developed primarily for their ability to infect and destroy cancer cells while sparing healthy tissue. Research has since expanded their potential role by exploring how engineered viruses can also deliver therapeutic genetic payloads and stimulate immune activity within tumors.
The longstanding challenge has been systemic delivery. Many viral therapies can be identified and cleared by the immune system before they circulate long enough to reach tumors following intravenous administration. Advances designed to overcome this limitation could broaden the role of virotherapy beyond localized treatment and create new opportunities for targeted delivery of genetic medicines.
Turning Tumors Into Sites Of Therapeutic Production
One particularly promising direction in oncology research is using targeted delivery systems to generate therapeutic agents directly within tumors. Instead of administering an immune-stimulating agent broadly throughout the body, an engineered therapy can potentially carry the genetic instructions for that agent to the tumor and produce it within the tumor microenvironment. This creates an opportunity to achieve high levels of therapeutic activity where it is needed while maintaining lower circulating levels elsewhere in the body.
At Calidi Biotherapeutics, this principle is being explored through an in-house platform, which systemically delivers virotherapy engineered to evade immune clearance, selectively target tumors, and deliver genetic payloads within the tumor microenvironment.
Our lead program, CLD-401, is engineered to express an IL-15 superagonist within tumors. IL-15 is a cytokine associated with activation of CD8 T cells, gamma delta T cells, and natural killer cells. In preclinical studies, CLD-401 has demonstrated high intratumoral IL-15 expression alongside low circulating levels, as well as recruitment and activation of NK, NK-T, and gamma delta T cells within the tumor microenvironment.
Building More Flexible Therapeutic Platforms
Using targeted delivery systems to generate therapeutic agents directly within tumors also has implications for how oncology drugs are discovered and developed. A delivery platform capable of carrying different genetic payloads creates the potential to adapt therapeutic strategies based on tumor biology rather than developing an entirely new delivery system for every therapeutic mechanism.
Cytokines are one example, but researchers are also exploring other payloads capable of altering immune activity within tumors. At Calidi, we are evaluating the potential of our platform to deliver multiple genetic payloads exclusively to the tumor microenvironment. These payloads include cytokines like IL-15 superagonist or T cell engagers expressed in situ. This type of platform approach could allow researchers to pair advances in cancer biology with delivery technologies capable of concentrating their effects at the disease site. It may also create opportunities for targeted virotherapies to complement other areas of oncology, including existing immunotherapies, cell therapies, and precision medicines. Rather than viewing these modalities as competing approaches, future treatment strategies may combine technologies that address different aspects of tumor biology and therapeutic delivery.
The Next Chapter Of Oncology R&D
The oncology field has become precise in identifying the molecular and immunological mechanisms that drive cancer. The next challenge is translating that knowledge into therapies that can consistently reach tumors and generate the intended biological response.
For drug developers, this means delivery, therapeutic mechanism, and the tumor microenvironment must be considered as interconnected components of the same development challenge. Targeted immunotherapies and genetic medicines offer an opportunity to rethink that relationship. By designing therapies capable of reaching tumors systemically and concentrating therapeutic activity within the tumor microenvironment, researchers may be able to expand the range of mechanisms that can be pursued while addressing some of the limitations associated with systemic exposure. Substantial scientific and clinical work remains before these approaches can reach their full potential, but advances in targeted delivery could help expand what is possible in cancer drug discovery and support the development of more precise treatment strategies.
About The Author
Eric Poma, Ph.D., has served as CEO and a board director of Calidi Biotherapeutics since April 2025. He brings more than 30 years of biopharmaceutical industry experience spanning capital raising, strategic partnerships, and clinical development. Prior to Calidi, he served as CEO of Molecular Templates, where he raised more than $250 million in equity financing and secured over $150 million through collaborations with Takeda, Vertex, and Bristol Myers Squibb. Earlier roles included leadership positions at Innovive Pharmaceuticals and ImClone Systems. Poma holds a Ph.D. in microbiology and immunology and a B.S. in biology from the University of North Carolina at Chapel Hill, as well as an MBA from New York University’s Stern School of Business.