Principal Investigator: Dr. Heather McArthur, M.D.
UT Southwestern Medical Center
Project title: “A phase 2 study of peri-operative immune therapy and cryoablation in women with hormone receptor-negative, HER2-negative early stage/resectable breast cancer.”
Immune therapy has recently become a cornerstone of curative intent therapy for patients with residual hormone receptor-negative, HER2-negative breast cancer (“triple-negative”, TNBC) when administered with chemotherapy. However, while this important recent treatment advance has significantly improved cure rates for patients with TNBC, approximately one-third of patients who do not completely respond to pre-operative therapy will experience a life-threatening recurrence within three years. The clinical challenge is further complicated by growing evidence that TNBC is a diverse disease where responses to therapy can vary widely between patients. Therefore, strategies that further optimize responses to immune therapy are needed.
Preclinical studies led by collaborator and Nobel Laureate, Dr. James Allison, demonstrated that destruction of tumor tissue by cryoablation (tumor freezing) induces activation and maturation of critical immune cells and subsequent activation of tumor-specific immune cells. Moreover, concurrent stimulation of the immune system with immune therapy enhanced the magnitude and potency of the immune response. Based on this data, Dr. Heather McArthur led two pilot studies of preoperative cryoablation combined with immune therapy in patients with early-stage breast cancer. Based on the success of these pilot studies she has since undertaken a phase 2 study of cryoablation plus immunotherapy in patients with TNBC who do not achieve a complete response after conventional pre-operative chemotherapy with immune therapy(NCT03546686). Enrolled patients undergo cryoablation, which is administered 7 to 10 days prior to surgery. Broadly, she and her colleagues hypothesize that the biology of an individual patient’s tumor and immune system can be exploited with cryoablation and immune modulation to confer long-term tumor-specific immunity, and ultimately cure.
One of the strengths of this study is the serial tissue collection, with specimens collected prior to cryoablation and then at surgery. With her collaborator, Dr. Isaac Chan, they have created a novel platform that will enable them to generate patient-derived organoids (organ-like) cultures of breast cancer patient biopsies that can be studied in the laboratory.These mini-tumors capture the diverse nature of a person’s breast cancer and allows the investigators to then study interactions with various immune cells to better understand potential influences on treatment responses, metastatic potential and even toxicity. This platform is a technological advance from other assays because it models dynamic interactions in real-time using patient-derived tumors. This revolutionary technology permits us to interrogate the local response within the tumor and the systemic response to the intervention. In this way, Dr. McArthur and her team will have completed the cycle of learning by taking the insights from the bench to the bedside (i.e. by successfully implementing a uniquely innovative clinical trial) and then back from bedside to bench (i.e. by creating organoids from each trial participant). Their overarching hope is that they will not only improve cure rates for TNBC but also learn directly from each individual experience.
The first 6 months of the B-SEARCH funding initiative supported the enrollment and successful treatment of 7 women on study, the successful procurement of equipment and materials necessary to generate the patient-derived organoids, and the hiring of laboratory staff to facilitate the organoid development. Biopsies from all 7 patients were obtained prior to the tumor freezing procedure and the patient-derived organoids are being developed. Future funding will be instrumental in supporting completion of enrollment with treatment for 20 additional patients on study planned within the funding period, organoid generation for enrolled patients, analyses of scientific findings and reporting.
UT Southwestern Medical Center
Project title: “A phase 2 study of peri-operative immune therapy and cryoablation in women with hormone receptor-negative, HER2-negative early stage/resectable breast cancer.”
Immune therapy has recently become a cornerstone of curative intent therapy for patients with residual hormone receptor-negative, HER2-negative breast cancer (“triple-negative”, TNBC) when administered with chemotherapy. However, while this important recent treatment advance has significantly improved cure rates for patients with TNBC, approximately one-third of patients who do not completely respond to pre-operative therapy will experience a life-threatening recurrence within three years. The clinical challenge is further complicated by growing evidence that TNBC is a diverse disease where responses to therapy can vary widely between patients. Therefore, strategies that further optimize responses to immune therapy are needed.
Preclinical studies led by collaborator and Nobel Laureate, Dr. James Allison, demonstrated that destruction of tumor tissue by cryoablation (tumor freezing) induces activation and maturation of critical immune cells and subsequent activation of tumor-specific immune cells. Moreover, concurrent stimulation of the immune system with immune therapy enhanced the magnitude and potency of the immune response. Based on this data, Dr. Heather McArthur led two pilot studies of preoperative cryoablation combined with immune therapy in patients with early-stage breast cancer. Based on the success of these pilot studies she has since undertaken a phase 2 study of cryoablation plus immunotherapy in patients with TNBC who do not achieve a complete response after conventional pre-operative chemotherapy with immune therapy(NCT03546686). Enrolled patients undergo cryoablation, which is administered 7 to 10 days prior to surgery. Broadly, she and her colleagues hypothesize that the biology of an individual patient’s tumor and immune system can be exploited with cryoablation and immune modulation to confer long-term tumor-specific immunity, and ultimately cure.
One of the strengths of this study is the serial tissue collection, with specimens collected prior to cryoablation and then at surgery. With her collaborator, Dr. Isaac Chan, they have created a novel platform that will enable them to generate patient-derived organoids (organ-like) cultures of breast cancer patient biopsies that can be studied in the laboratory.These mini-tumors capture the diverse nature of a person’s breast cancer and allows the investigators to then study interactions with various immune cells to better understand potential influences on treatment responses, metastatic potential and even toxicity. This platform is a technological advance from other assays because it models dynamic interactions in real-time using patient-derived tumors. This revolutionary technology permits us to interrogate the local response within the tumor and the systemic response to the intervention. In this way, Dr. McArthur and her team will have completed the cycle of learning by taking the insights from the bench to the bedside (i.e. by successfully implementing a uniquely innovative clinical trial) and then back from bedside to bench (i.e. by creating organoids from each trial participant). Their overarching hope is that they will not only improve cure rates for TNBC but also learn directly from each individual experience.
The first 6 months of the B-SEARCH funding initiative supported the enrollment and successful treatment of 7 women on study, the successful procurement of equipment and materials necessary to generate the patient-derived organoids, and the hiring of laboratory staff to facilitate the organoid development. Biopsies from all 7 patients were obtained prior to the tumor freezing procedure and the patient-derived organoids are being developed. Future funding will be instrumental in supporting completion of enrollment with treatment for 20 additional patients on study planned within the funding period, organoid generation for enrolled patients, analyses of scientific findings and reporting.
