Injecting Cancer Killers: Intratumoral Therapy For Solid Tumors
By Lew Bender, founder and CEO, Intensity Therapeutics, Inc.
For decades, the standard of care for metastatic cancer has been systemic drug delivery through the bloodstream that reaches every corner of the body. While this is effective for blood cancers, solid tumors, like those found in the lung, pancreas, or breast, are essentially biological fortresses. Solid tumors create a microenvironment characterized by high internal pressure and dense structural barriers that physically push drugs away, meaning systematic administration wreaks havoc on the bodies of those forced to undergo treatment.
Furthermore, many of these tumors are cold, meaning they have evolved to be immune deserts. The cancer cells lack the inflammatory signals needed to attract immune cells, allowing the cancer to grow undetected. When we give potent immunotherapies intravenously, we often face a common catch-22: we must increase the dose to force the drug to bind to more immune cells, but those high concentrations of activated immune cells circulate through the entire body, causing off-target toxicities that damage healthy organs without the cancer being attacked sufficiently.
Millions across the country who unfortunately develop cancer face an untenable dilemma: face the complications from cancer or face the incredibly toxic treatment that could leave their bodies permanently damaged. The result is very similar to the story of Christine Handy, somebody I’ve had the privilege of working with these past few years, whose story is all too common in this realm, where breast cancer treatment has left her with permanent cardiac damage.
The Mechanism: Engineering An In Situ Vaccine
My vision for intratumoral injection started in 2012. I knew that intratumoral injection had been attempted many times before. However, due to the high fat content, pressurized and dense structure of most solid tumors, injection of water-based products was unlikely to be successful because water and fat do not mix. I leveraged my previous training in novel chemistry to develop INT230-6, a formulation containing proven cytotoxic agents (cisplatin and vinblastine) and a dispersion and cell-penetration enhancer molecule to help the tumor absorb the potent killing agents. Upon injection, INT230-6 disperses throughout the tumor and diffuses into the cancer cells. With this concept of a new chemistry, Intensity Therapeutics was born.
Intratumoral injection flips the script on the way we’ve historically targeted solid tumors. By using a needle to deliver a diffusive therapy directly into the heart of a lesion, we bypass the tumor’s physical defenses entirely. The goal is to help patients live longer, with a high quality of life and without the fear of being harmed by the treatment. Ours is more than just a first-in-class cancer drug product. We are changing the concept of how to treat metastatic and local disease.
Directly injecting a drug into the solid tumor, based on the size of the tumor or a patient’s total tumor burden, kills the bulk of the cancer cells with minimal side effects and activates a potent personalized anti-cancer immune response. We have published our first clinical results, which clearly demonstrate the potential of our new approach.
However, the true magic isn't just the delivery, it’s the biological "reprogramming" that follows. INT230-6 was specifically designed for intratumoral delivery. After direct injection, the drug saturates the cancer cells with the potent agents and causes tumors to die. Then, the immune system begins to recognize the cancer. Cisplatin and vinblastine have dual killing and immune-activating mechanisms of action. With the proper dose into the tumor, these drugs can cause the majority of cancer cells to die in an immunologically activating manner. The debulking process of our drug then creates a T cell attack on the injected and uninjected tumors.
When we inject a combination of cancer-killing agents directly into a tumor, we are essentially creating a personalized antigen, chemicals that can be used to train immune cells to fight the cancer. These signals act as a flare gun for the immune system, teaching local dendritic cells and T cells exactly what the cancer looks like. Once educated, these immune cells enter the bloodstream to seek and destroy cancer cells in the injected tumor and distant untreated parts of the body. This allows a local treatment to have a truly systemic impact.
The move toward intratumoral delivery has opened the door for combinations that may be too toxic if given through intravenous administration (IV) alone. Cancer researchers are no longer limited to a single drug, they can use multimodal toolkits such as oncolytic viruses, checkpoint inhibitors to jump start immunoresponses, and other types of gene and mRNA therapy.
Clinical Advantages: High Potency, Low Toxicity, And The Precision Of Modern Imaging
From a clinical perspective, the transition to intratumoral delivery based on a new diffusion delivery technology that activates a systemic immune response is transformative because it solves the therapeutic window problem — the narrow margin between a dose that kills cancer and a dose that harms the patient. By delivering therapy directly to the source, we can achieve drug concentrations at the tumor site that are often 100 times higher than what is possible via IV, yet with only a fraction of the systemic circulation.
The systemic immune response that follows comes from providing personalized high-quality antigen. This means we can use more aggressive multi-drug killing agents in the intratumoral product while significantly reducing the risk of organ stress and chronic fatigue for the patient. Thinking back to the example of my colleague Christine Handy, intratumoral injection prior to any further treatment could have led to a much better outcome without the toxic cardiac side effects.
A common misconception in this field is that intratumoral injection is limited to visible skin lesions like melanoma. In reality, the field of interventional oncology has turned deep-seated tumors into accessible targets. Using real-time high-definition imaging, clinicians can now navigate needles into internal organs with millimeter precision.
This precision is particularly revolutionary for neoadjuvant care, which is treatment given before a primary tumor is surgically removed. By injecting a tumor while it is still in the body, we essentially use the tumor as a classroom for the immune system, where the T cells learn to recognize the specific mutations of that patient's cancer. When the surgeon eventually removes the physical mass, the patient is left with a primed immune system and an internal security force already trained to seek out and mop up any microscopic cancer cells that may have escaped into the bloodstream, potentially preventing a recurrence in the future.
Conclusions
Intratumoral injection is not a panacea for every cancer. There will be some tumors that cannot be injected and some instances where our drug just will not be effective. Examples include tumors that are too diffuse, certain types of blood cancers, or one of many other complications that will not make it feasible.
However, there are many cancers that will be amenable to this treatment, where it can have a real impact and make a significant difference for patients. Intensity Therapeutics is now in a randomized, controlled, Phase 3 clinical trial treating metastatic sarcomas with INT230-6 as monotherapy, compared with the best standard-of-care systemic drugs, a first of its kind trial. The efficacy endpoint is overall survival. That is and should be the main goal of cancer researchers today: allowing patients to live longer, with a high quality of life and without the fear of being harmed by the treatment.
About The Author
Lew Bender is founder and CEO of Intensity Therapeutics. He has more than 32 years of biopharmaceutical leadership experience and has helped take products from discovery through product approval, leveraging novel drug delivery techniques. Lew pioneered Intensity and its foundational science in his basement. Including Intensity, he has been CEO of two other public biotech companies, a personalized medicine company (IG) and a drug delivery company (Emisphere). During his career, Lew held numerous positions in addition to the CEO role, including head of business development, manufacturing, process development, regulatory affairs, and quality control.