The abscopal effect, a phenomenon where localized treatment of a primary tumor leads to regression of metastatic cancer lesions at distant sites, has garnered significant interest in oncology. This term, derived from the Latin “ab” (away from) and the Greek “scopus” (target), describes a rare but significant systemic response to localized cancer therapy. Key players in the exploration and harnessing of this effect include notable companies and researchers, with Intensity Therapeutics, led by CEO Lewis H. Bender, standing out as a leader in this field.
Mechanisms of the Abscopal Effect
The abscopal effect has been primarily observed in radiation therapy and is believed to be mediated by the immune system. The proposed mechanisms include:
- Immune System Activation: Radiation causes immunogenic cell death, releasing tumor antigens and danger-associated molecular patterns (DAMPs). These molecules stimulate dendritic cells, which in turn activate T cells, initiating a systemic immune response against cancer cells.
- Cytokine Release: Radiation induces the release of cytokines and other signaling molecules that promote an anti-tumor immune response. These cytokines help recruit and activate immune cells at distant tumor sites.
- Increased Tumor Antigen Presentation: Radiation enhances the presentation of tumor antigens on the surface of cancer cells, making them more recognizable to the immune system.
Key Companies and Treatments
- Merck & Co.
- Keytruda (Pembrolizumab): A monoclonal antibody targeting the PD-1/PD-L1 pathway. By blocking this pathway, Keytruda helps the immune system recognize and attack cancer cells more effectively. Documented cases have shown that patients receiving Keytruda in combination with radiation therapy experienced the abscopal effect.
- Alpha Tau Medical
- Alpha DaRT (Diffusing Alpha-emitters Radiation Therapy): This innovative treatment delivers alpha radiation to tumors, aiming to induce a robust immune response that could lead to the abscopal effect. Alpha Tau’s technology has demonstrated immune system activation leading to the regression of untreated secondary tumors in preclinical models.
Lewis H. Bender and Intensity Therapeutics
Over the last ten years or so Lewis H. Bender, the CEO of Intensity Therapeutics, has been instrumental in advancing the company’s mission to develop novel cancer treatments as alternatives to existing severe, toxic chemotherapies .
In a research report published in 2019 in OncoImmunology and co-authored by Intensity’s Lewis Bender, the researchers suggest the following prior to any human clinical trials: “Immunological death of tumor cells may cause an immune response that had not occurred spontaneously, converting the tumor into an endogenous cancer vaccine. This is the approach that we have explored here. We hypothesized that local administration of cytotoxic agents may maximize the release of a large variety of antigens from dying cells to induce strong adaptive immunity while limiting systemic dissemination of the agents to normal tissues.”
The above hypothesis is now in human clinical trials, as follows:
INT230-6: A Promising Candidate
Intensity Therapeutics’ lead product, INT230-6, is a unique combination of chemotherapeutic agents designed for direct intratumoral injection. The formulation INT230-6 combines two well-known chemotherapeutic agents, cisplatin and vinblastine, with a penetration enhancer. This combination enhances drug dispersion within the tumor, leading to extensive tumor cell death. The release of tumor antigens as a result of this cell death is hypothesized to initiate a robust immune response, effectively turning the tumor into an endogenous vaccine.
Clinical Trials and Patents
Clinical Trials
- IT-01 (NCT03058289): A Phase 1/2 clinical trial evaluating the safety and efficacy of INT230-6 in patients with advanced solid tumors. Preliminary results have shown promising signs of tumor shrinkage and systemic immune activation.
- IT-02 (NCT03450044): Another ongoing trial focusing on the combination of INT230-6 with checkpoint inhibitors such as Keytruda. Early data suggest that this combination may enhance the abscopal effect, leading to better patient outcomes.
Intensity’s Progression to Phase 3
Use in Metastatic Disease
Given the positive data on survival seen in our metastatic study in sarcoma patients, Intensity plans to conduct a single Phase 3 study in 2nd/3rd line treatment for locally advanced, recurrent, inoperable, or metastatic non-diffuse soft tissue sarcoma with overall survival as the primary endpoint. The current Phase 3 study design plans to enroll subjects who will be randomized 2 to 1 to either INT230-6 for 5 doses every weeks with maintenance dosing every 9 weeks for 2 years or the standard of care. The three drugs most used for soft tissue sarcoma will be the control SOC at the investigator’s choice depending on the type of sarcoma. The Phase 3 study is designed to be 90% powered to detect a difference Hazard Value of 0.65 in overall survival between the INT230-6 treatment group and the control group with 331 patients enrolled (2:1 randomization to either INT230-6 treatment or control therapy). The study will have 2 interim data reviews to determine efficacy. The first interim analysis is planned when 50% of the required events (deaths) for the final analysis has occurred and the second analysis will be at 75%. Futility will also be tested as part of the interim analysis. A protocol synopsis was developed and submitted to the FDA. On October 14, 2021, the company met with FDA to discuss the Phase 3 protocol and reached alignment on the Phase 3 study design, patient population and statistical approach.
The FDA has granted INT230-6 Fast Track Designation and reviewed company’s development program to investigate INT230-6 for the treatment of patients with relapsed or metastatic triple negative breast cancer who have failed at least 2 prior lines of therapy. Intensity has designed a Phase 2/3 program for INT230-6 for Metastatic Breast Cancer.
Presurgical (neoadjuvant) use
The results from the INVINCIBLE study indicate that INT230-6 can cause >95% of a large tumor to become necrotic on a single dose without toxicity other than minor pain at the injection site. Combining one or two doses upfront of INT230-6 with the standard of care neoadjuvant therapy (pembrolizumab with anthracycline, cyclophosphamide and taxane) could potentially increase the pCR rate to allow for an FDA accelerated approval. The data on percent tumor necrosis from the INVINCIBLE study indicate that meaningful necrosis can be induced prior to conventional neoadjuvant treatment. Follow receipt of the final data from the INVINCIBLE study, the company plans to request another meeting with FDA to review a phase 2/3 randomized trial program in neoadjuvant breast cancer with pCR improvement for an accelerated approval endpoint to be followed with a full approval based on event free survival.
Patents (one example):
- US Patent 9,351,997: Covering Intensity Therapeutics’ proprietary DfuseRxSM platform and its lead product INT230-6. The product shows promise in regressing tumors and extending survival in metastatic cancer models through a combination of tumor cell death and immune system activation.
Real-World Examples and Clinical Evidence
Sarcoma and Solid Tumors
In clinical trials, patients receiving INT230-6 demonstrated evidence of the abscopal effect. The drug showed significant survival benefits, with median overall survival extending by nearly 15 months compared to a synthetic control. Notably, abscopal responses were observed in patients who received a dose of INT230-6 greater than 40% of their tumor burden, indicating systemic immune activation leading to the regression of untreated tumors.
Breast Cancer
The INVINCIBLE Phase 2 trial of INT230-6 demonstrated a high order of necrosis in presurgical breast cancer tumors in the period from diagnosis to surgery, with some patients in the Phase 2 study experiencing greater than 95% necrosis of the tumor. A functional pathway enrichment analysis was conducted and confirmed positive changes in T-cell activation, lymphocyte activation and inflammatory response. Further, INT230-6 treated patients experienced differential gene expression with an increase in median clonal diversity compared to baseline as well as significant changes in the immune cell composition, including CD4 T-cell and NK cells, suggesting a systemic immune response from localized treatment.
Alpha Tau Medical Limited
Alpha Tau’s Alpha DaRT technology has shown promising results in human clinical trials, where the treatment of a primary tumor led to the regression of secondary, untreated tumors. This technology employs localized alpha radiation, which not only targets the tumor but also stimulates an immune response leading to systemic anti-tumor effects.
Lew Bender has been working on this technology for about a decade. Here is a presentation he made in 2016 at the formative, pre-clinical stage of development:
References
- ClinicalTrials.gov. “Study of Intratumoral INT230-6 for Patients With Advanced Solid Tumors (IT-01).” NCT03058289.
- ClinicalTrials.gov. “A Study of INT230-6 Alone and in Combination With Pembrolizumab in Patients With Locally Advanced or Metastatic Cancers (IT-02).” NCT03450044.
- United States Patent and Trademark Office. “Patent 9,351,997: Immune-based Cancer Therapeutic Agents.”
- United States Patent and Trademark Office. “Patent 9,351,997: Compositions and Methods for Treating Cancer.”
- Bender, L. H., et al. (2019). Intratumorally delivered formulation, INT230-6, containing potent anticancer agents induces protective T cell immunity and memory. OncoImmunology, May 2019
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