How Can We Develop New Treatments For Patients With Early Breast Cancer?
By Lewis H. Bender, CEO, Intensity Therapeutics
While breast cancer (BC) rates in younger women are rising, so is the number of women with a highly aggressive form of the disease, known as triple negative. In this BC subtype, women test negative for three surface proteins (progesterone, estrogen, and Her2), which limits the number of medicines that can treat the patient’s cancer. Undergoing chemotherapy with immunotherapy for early-stage triple-negative breast cancer (TNBC) before surgery is now the standard of care and referred to as neoadjuvant immunochemotherapy (NAIC). NAIC aims to eliminate viable cancer in the tumor, lymph nodes, and possible distant metastases; shrink tumors to improve surgical outcomes; and prevent disease recurrence. In 2017, Merck’s Keynote-522 study showed that the addition of immunotherapy increased three-year event-free survival in patients with early-stage TNBC using NAIC and slightly improved pathological complete response (pCR) rates. A pCR means no cancer is left at the time of surgery in the tumor or any lymph nodes. However, this NAIC regimen is highly toxic, with 80% of women having a grade 3 adverse event that often requires hospitalization for a short period.
Doxorubicin is used in several chemotherapy regimens for many breast cancer subtypes, including TNBC, before surgery (neoadjuvant). Doxorubicin also can be used in early-stage breast cancer after surgery or in metastatic breast cancer. Patients call this drug the “red devil” for its harsh red color and side effects, which include fatigue, nausea, hair loss, and permanent heart damage.
We need new drugs that can increase pCR, as this marker has been shown in several studies to reduce the risk of disease recurrence. An increase in pCR rate is accepted by regulatory authorities (including FDA) around the world for accelerated approval, as several studies (Cortazar, CALGB) have shown that at five years after surgery, a patient having a pCR has a 16% risk of the disease returning compared to a 50% risk of recurrence for those without a pCR.
A Combination Therapy Approach: An Intratumoral Treatment + Chemotherapy
Intensity Therapeutics has developed a new approach to treating cancer — a therapy injected directly into tumors that kills cancer and stimulates a potent anticancer immune response. The idea is to debulk as many visible tumors as possible and use the systemic immune response to contain or eliminate the uninjected and invisible tumors. When combining our novel drug product, INT230-6, with the current immune/chemotherapy of Keynote 522, perhaps women will have more pCRs and less toxicity.
The concept of administering an intratumoral (IT) treatment is not new; however, current and past IT methods fail to address the key fact that a tumor’s lipophilic, high-fat, and pressurized microenvironment does not effectively absorb water-based products. Prior and current IT treatments formulated their product candidates as aqueous products (regardless of the mechanism or approach), while other current IT efforts attempt to stimulate an inflammatory response or attract immune cells into a hostile live tumor. However, the fundamental challenge of IT treatment is drug delivery. Intensity discovered that a class of molecules with amphiphilic properties used primarily for oral delivery of peptides, such as GLP-1, had the properties needed to disperse drugs throughout tumors and into cancer cells. These molecules were originally used to create oral products of proteins and peptides, but our patents cover the intratumoral application.
Our lead product candidate, INT230-6, consists of two proven anti-cancer cytotoxic agents, cisplatin and vinblastine sulfate, mixed in water with the amphiphilic molecule 8-[(2-hydroxybenzoyl)amino] octanoate (referred to as SHAO). The FDA previously approved both drugs as intravenous agents for several types of cancers. Cisplatin was first approved in 1978 and is used widely in several cancers, including breast cancer. Platinum compounds, like cisplatin, are alkylating agents, which bind to the DNA inside of cells and cause a kink in the DNA chain. This kinking of the DNA results in the cell thinking there is a defect, which triggers a self-destruct mechanism (apototic cell death). Cisplatin is likely the most potent platinum compound. When given intravenously, the toxicity to healthy tissues can be quite high and strong, which is why other platinum agents were developed. However, when given intratumorally and delivered into the cancer cell, cisplatin affects the tumor rather than the healthy tissue.
Vinblastine sulfate was approved in 1965. Today, the drug is still used in several cancers (breast, lung, etc.). Vinblastine is a potent destroyer of tubulin, the component of the cell that causes its replication. By shredding the tubulin, the cell loses its ability to reproduce and eventually dies. As in the case of cisplatin, delivery of vinblastine directly into the tumors allows for the full power of the drug to destroy the cancer cells with devasting effect. Both drugs can activate different functions of the immune system to direct immune cells to fight the cancer not only in the tumor but also in the entire body.
Intensity was awarded a Collaboration Research and Development Agreement (CRADA) by the NIH’s National Cancer Institute to better understand the mechanism of action of the intratumoral drug that is now INT230-6. NCI reported that INT230-6 was synergistic with anti-PD-1 (programmed death receptor 1) and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies.
Could This Be A Safer, More Effective Approach To Breast Cancer Treatment?
INT230-6 has already generated solid evidence of activity as a single agent in clinical studies. Data generated in mice has translated well in humans. Localized and abscopal effects have been observed in several patients. Tumor regressions with killing of the cancer cells is widely observed in injected lesions. Many patients who had exhausted all approved treatments for their type of cancer benefited from our product candidate. Our clinicians have reported tumor stabilization, tumor shrinkage, long periods without new tumors forming, a size reduction of uninjected tumors, and a reduction in disease symptoms. These results are observed in combination with low toxicity over a period of several months and even well after our treatment has completed.
Continued preclinical testing has identified improved formulations that may lead to better results than those already achieved. Late-stage studies are underway using INT230-6 that could prove that this new intratumoral product creates a safer, more effective breast cancer treatment. Perhaps someday a regimen can be approved that eliminates the red devil for most cancers.
About The Author
Lew Bender, CEO and founder of Intensity Therapeutics, is an MIT-trained chemical engineer and seasoned biotech leader with a track record of innovation. Driven by a desire to improve outcomes for cancer patients, Bender stepped away from a successful biopharmaceutical career to pursue a bold idea he later developed in his basement: delivering cancer-fighting drugs directly into tumors to kill cancer cells and spark an immune response. Today, his idea has grown into a global Phase 3 clinical program and 14 patents across 41 countries and all major markets.