Treating BC Brain Metastases with Cytotoxic Lymphocytes

Institution: Sidney Kimmel Cancer Center
Investigator(s): Barbara Mueller, Ph.D. - Barbara Mueller, Ph.D. -
Award Cycle: 2008 (Cycle 14) Grant #: 14IB-0045 Award: $186,496
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

This is a collaboration with: 14IB-0045A -

Initial Award Abstract (2008)

Women with breast cancer are living longer and experiencing an improved quality of life because powerful new therapies can control metastases in many sites including liver, lung and bone. At the same time breast cancer metastasis to the brain is being diagnosed more frequently because these systemic therapies do not prevent or control brain metastasis. For many women with advanced breast cancer, brain metastases present the greatest conceivable threat. Our interest is to explore a novel type of immunotherapy to treat brain metastasis. For this we will create cytotoxic lymphocytes (CTL) from healthy donors that are “trained” in the laboratory to recognize “Human Leukocyte Antigens” (HLA) from breast cancer cell lines. This approach is particularly useful in cancer sites where the normal cells express little or no HLA, such as gliomas.

First, we will generate alloCTL from peripheral blood mononuclear cells (PBMC) from human donors against breast cancer cell lines with the propensity to metastasize to the brain (BCM2 BrainG2, MDA-MB-231-1883) using established stimulation protocols. The cytotoxicity of alloCTL against relevant tumor targets and irrelevant controls will be determined by standard assays. Next, the alloCTLs will be induced to proliferate in response to incubation with relevant breast cancer brain metastasis antigen targets. HLA expression on breast cancer targets will be increased with interferon or knocked down by RNA interference to establish alloCTL cytotoxicity relative to the level of HLA expression. Then, the migration of alloCTL will be examined in SCID mice with intracranial human breast tumor foci. We will evaluate the spread of alloCTL after intratumoral injection and the trafficking to distant tumor foci in the brain. Finally, the efficacy of alloCTL in eradicating breast tumor foci in the brain will be determined by volumetric analyses.

AlloCTL have never been evaluated fosr the treatment of breast cancer metastasis to the brain. Therefore the proposed project is novel and unique. However, alloCTL technology has been worked out in the context of primary brain tumors and we are very hopeful that similar conditions can be found for the treatment of breast cancer metastasis to the brain. In this regard the proposed project is feasible and its translation into the clinic will not require any technological leaps.




Final Report (2010)

Women living longer with breast cancer are now frequently diagnosed with brain metastases. Current treatments for brain metastases are ineffective and there is a need for new therapeutic strategies. We propose that allo-reactive cytotoxic lymphocytes (alloCTL) may be effective as a therapy for brain metastases. alloCTL are lymphocytes from an unrelated blood donor that are trained to recognize cancer cells as “foreign” and kill them, not unlike what happens in the rejection of an organ transplant from an unrelated individual. The goals of this research project was to evaluate the functionalities and characteristics of human alloCTL generated against human breast cancer cells in cell culture and to determine the therapeutic efficacy of alloCTL delivered to breast tumors growing in the brains of mice.

With funding from the CBCRP we have established a robust protocol to generate alloCTL from unrelated blood donors directed against human breast cancer cells. We have characterized the resulting alloCTL for their immunological markers and have demonstrated their ability to specifically kill breast cancer cells including those with high propensity to metastasize to the brain. We have established a mouse model in which the brain metastatic human breast cancer cell line MDA-MB-231BR grows intracranial tumors in immune deficient mice. In this model, treatment with alloCTL suppresses tumor growth. Intratumoral injection of alloCTL also prolongs the survival of mice with established intracranial breast tumors compared to untreated controls and to controls treated with unstimulated lymphocytes. We are currently evaluating the migratory ability that allows alloCTL to move through the brain and seek out breast cancer targets.

alloCTL are showing great promise clinically in patients with primary brain tumors. They may also be an effective and non-toxic therapy for brain metastases. The objective of our study was to establish proof-of-principle that alloCTL can effectively treat breast cancer in the brain. Encouraged by the results obtained we will apply for more support from the NIH/NCI to develop this research further. Ultimately this may lead to a new treatment modality for women with breast cancer metastatic to the brain.