Intratumoral Treatment Of Cancer: After Many Prior Attempts, Has The Time Finally Come?

By Lew Bender, Founder and CEO, Intensity Therapeutics

The Royal Society of Chemistry has reported that humans have had a long history of attempting to treat cancer locally with chemicals. The earliest reference the Society cites is from the Ebers Papyrus of 1500 BC, which advocated using arsenic-laden ointments to treat ulcerating, presumptively cancerous, lesions.¹

Ninety-five years ago, in 1931, Adair and Bagg tested an analog of sulfur mustard, the vesicant gas of World War I, for topical and intralesional treatment of numerous types of cutaneous malignant lesions.²

While results of tumor eradication from those experiments seemed positive, the approach went unpursued, possibly due to some blistering of the skin. Today, radiation or ablation techniques remain the primary methods for local treatment of cancer, despite radiation therapy for cancer frequently resulting in skin discoloration and burning, commonly known as radiation dermatitis.

A Look at How We Got Here

Over the past 30 years, multiple attempts at injecting a drug locally into tumors to treat either the lesion or sometimes metastatic disease have been explored. Those efforts usually combined local treatment with systemic drugs such as chemotherapy or immunotherapy. A wide variety of ideas, device approaches, and other technologies using various agents were tested clinically. A few notable efforts are listed below.

• Chemotherapy/small molecule/dye agents: cisplatin gel (Matrix), rose bengal/PV-10 (Provectus), taxane microparticles (NanOlogy)
• Oncolytic viruses (biologics): T-VEC/Imlygic (BioVex/Amgen), Reolysin (Oncolytics Biotech), teserpaturev/Delytact (Daiichi Sankyo), MVR-T3011 (ImmVira)
• Immune cell or cytokine therapies (biologics): ilixadencel, various dendritic cell products
• Agonists against proteins: The most common target was the stimulator of interferon genes (STING), a crucial protein in the body's innate immune system. Several companies made attempts at intratumoral delivery: Merck MK-1454 ulevostinag, Aduro Biotech (later merged into Chinook Therapeutics) ADU-S100 (MIW815), Eisai/H3 Biomedicine E7766, Boehringer Ingelheim BI1387446, and Takeda TAK-676. There were also agonists against the retinoic acid-inducible gene I (RIG-1) an innate immune receptor located inside the cell cytoplasm that detects viral infections by recognizing foreign RNA and the Toll-like receptor (TLR). A marketed product of these agonists has yet to appear.
• Nanoparticle radioenhancers: JnJ, in partnership with Nanobiotix, is testing NBTXR3, under the code JNJ‑1900, in a global Phase 3 study to treat locally advanced head and neck cancer. KORTUC Inc. (Japan) is testing its product, KORTUC (hydrogen peroxide + sodium hyaluronate), which was discovered at Kochi University, in Phase 2. Sichuan Enray Pharmaceutical Technology Co. (China) is developing CNSI‑Fe (ferrous ion–adsorbed carbon nanoparticle suspension) in a Phase 1 intratumoral-injection trial for advanced solid tumors.

As far as can be determined, only BioVex/Amgen’s product, T-VEC, has successfully achieved product approval from the FDA in the U.S. as a stand-alone therapy. The drug is approved for cutaneous, subcutaneous, and nodal melanoma (stages IIIB, IIIC, and IV-M1a) that can be injected directly and cannot be completely removed by surgery. Recently, Replimune’s intratumoral virus-based drug, vusolimogene oderparepvec-wtpg, was FDA-approved; however, approval applies only when the drug is used in combination with nivolumab (Opdivo) for treating adults with unresectable advanced cutaneous melanoma who progressed on an anti-PD-1.

The list of intratumoral therapy attempts is long, but the cancers where this approach applies are so far limited commercially to melanoma, which, according to analysis by the Broad Institute, is the most mutated cancer type — i.e., most different from a patient's own cells.³

The poor track record of developing commercial products using intratumoral delivery raises several questions. What are the scientific reasons why intratumoral delivery is such a sought after but rarely successful treatment option? Can intratumoral delivery be used beyond melanoma? What about metastatic disease? Can intratumoral delivery be used in this setting? Cancer kills over 620,000 Americans per year — the vast majority due to metastatic disease — and the need for better treatments is high. Is there a place for intratumoral drugs to treat cancer that has spread throughout the body? The answers may lie in the inherent physical properties of tumors and drug products.

Fat And Water Do Not Mix

First, let’s examine cancer’s properties. Tumors are derived from a patient’s healthy tissue. Cancer is a mutated form of the patient's cells. Depending on the type of cancer, the number of mutations can be significant. Therefore, we can consider tumors as an alien “cousin” invader of a patient’s body, triggered by the unique environmental exposures to the person’s DNA from carcinogenic agents over the course of a person’s lifetime. Tumors are dense, fatty, stromal, and often lack organized blood vessels or vascular structures. Tumors present to the immune system as “self,” and immune engagement is designed to avoid harming oneself. As a result, cancer often evades the immune response.

Drug products given to patients are typically water-based. Infusing drugs into the bloodstream demands a biocompatible vehicle. Water, as saline or dextrose solutions, matches blood's tonicity and pH range, avoiding damage to red blood cells, minimizing vein irritation, and avoiding widespread toxicity. Anything other than water-based fluid would be physiologically dangerous. Also, immunotherapies, antibody-drug conjugates, and CAR-T-related products are proteins — these products would denature or aggregate in organic solvents, so they must be formulated in aqueous buffers. Some cancer drugs do use non-aqueous solvents, such as paclitaxel and docetaxel, which are lipophilic (fat-loving molecules) and require polyoxyethylated castor oil (Cremophor), surfactants, and alcohol to stay in solution. Even though these agents are usually solvent-based in their concentrated form, the drug gets diluted into large-volume saline or dextrose IV bags before infusion — so what actually enters the patient's bloodstream is mostly water, with only traces of residual solvent. And still Cremophor EL (in paclitaxel) is a well-known cause of hypersensitivity reactions.⁴

Ethanol content, even diluted, can matter in patients who need to avoid alcohol (e.g., certain liver conditions, recovering alcoholics, pediatric patients). Newer formulations using drug delivery have found a work around this: nab-paclitaxel (Abraxane) uses albumin-bound nanoparticle technology instead of Cremophor to avoid solvent-related toxicity and the need for premedication. The short answer is that water dominates drug product formulations because of biocompatibility and solubility for dosing.

So, one can quickly understand the immediate problem with intratumoral delivery of drugs. The dense, pressurized, fatty, poorly vascularized environment of a tumor is nearly completely incompatible with the properties of a water-based drug. In short, water and fat do not mix. Past intratumoral efforts have overlooked the important physical differences and chemical incompatibility between tumors and drug products. Formulating water-based products for injections into dense fat tissue is the challenge. I first authored a paper published in the International Journal of Molecular Sciences in 2020⁵ noting this issue.

Where Do We Go From Here?

There is some positive news. Several companies are in Phase 3 development of intratumoral drug products, all with a lead product in a cancer other than melanoma, based on novel chemistry and a desire to preempt more harmful treatment options.

Candel Therapeutics is developing a modified virus, CAN-2409, that's injected directly into prostate cancer with a companion pill (valacyclovir) in combination with standard radiation therapy. CAN-2409 is used for localized prostate cancer — meaning the cancer hasn't spread outside the prostate.⁶ Specifically, it is for patients with intermediate- to high-risk localized disease. (Such a delivery vehicle [virus] may lower risk to the approval given that Amgen’s approved intratumoral product, T-VEC, is a virus for local cutaneous melanoma.). Results from a Phase 3 trial showed that CAN-2409, valacyclovir, and radiation resulted in longer disease-free survival than placebo plus valacyclovir when added to standard radiotherapy for localized prostate cancer.

Johnson & Johnson/Nanobiotix are in Phase 3 with JNJ-1900 (NBTXR3), a product composed of functionalized hafnium oxide nanoparticles administered via one-time intratumoral injection and activated by radiotherapy. The two firms are conducting a global open-label, randomized, two-arm, investigator's choice Phase 3 (pivotal stage) study to investigate the efficacy and safety of the nanoparticles/radiation therapy (RT) ± cetuximab versus RT ± cetuximab in treatment-naïve, platinum-ineligible, elderly participants with locally advanced head and neck squamous cell carcinoma. The endpoint is progression-free survival, defined as the time from randomization to local-regional progression (including recurrence), distant progression, or death from any cause, whichever occurs first, as determined by central review.⁷

Intensity Therapeutics is conducting a randomized, global controlled Phase 3 study using INT230-6, a single-vial product comprising cisplatin and vinblastine sulfate co-formulated with a tissue diffusion and a cell penetration enhancer, SHAO, in a fixed ratio. SHAO allows the cytotoxic agents in the 100% water-based product to dissolve in both fat and water simultaneously, dispersing the two potent anticancer agents throughout the tumor and diffusing them into cancer cells. Each cytotoxic agent has both direct-killing and immune-activating properties. The recruiting Phase 3 trial compares overall survival with INT230-6 monotherapy versus United States standard-of-care (SOC) drugs in participants with unresectable or metastatic liposarcoma, undifferentiated pleomorphic sarcoma, or leiomyosarcoma who have progressed before study enrollment after no more than two standard therapies.⁸

The Candel and the JnJ/Nanobotix trials are for local disease treatment with the new products combined with radiation and a second drug. Candel announced positive data, while JNJ/Nanobotix and Intensity are still recruiting for Phase 3.

The endpoint in Intensity’s Phase 3 study (INVINCIBLE-3) is overall survival. The decision to move INT23-6 alone into Phase 3 was based on data from nearly 110 patients with over 20 different types of refractory metastatic cancer. Results from a 64-patient monotherapy cohort of the trial showed that the local therapy controlled metastatic disease, activated a systemic anti-cancer immune response, and had potential for an overall survival benefit. There was a high rate of abscopal effects, meaning the uninjected lesions also shrunk. Results were published in the Lancet’s eBioMedicine journal. The authors of the Lancet paper believe this was the first time a local therapy given alone reported such outcomes.⁹

Each Phase 3 program described in this article is advancing intratumoral drug delivery. Candel has generated Phase 3 data for a treatment in locally advanced prostate cancer. JNJ and Nanobiotix have a treatment that could help meet the medical need of patients with locally advanced head and neck cancer. Intensity is testing its drug in metastatic sarcomas. All these programs are randomized controlled studies.

Recognizing that a technology to overcome the physical incompatibility between the tumor environment and water-based drug products may have been the key insight in understanding the intratumoral drug-delivery problem. If overall survival potential using only a locally delivered intratumoral product to treat metastatic disease observed in Intensity’s first study replicates in the Phase 3, it could be an important milestone for patients with sarcoma and potentially for those with other metastatic solid cancer types as well.

Together, the efforts of Amgen, Replimmune, Candel, JNJ/Nanobiotix, Intensity Therapeutics, and others may finally end over 3,500 years of frustratingly few commercial intratumoral products for patients with solid cancers other than melanoma and usher in a new era of cancer research.

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