Funded by the Stuart Scott Memorial Cancer Research Fund
Antibody treatments that block ‘immune checkpoints’ which prevent the immune system from fighting cancer, have resulted in impressive tumor shrinkage and long term survival in many patients with cancer. Results from studies in metastatic triple-negative breast cancer (TNBC) indicate promising activity but not yet the exceptional results seen in tumors known to be highly “immunogenic” or responsive to alterations in the immune system. Strategies to make TNBC “immunogenic” are therefore of great interest as they may result in long term control of TNBC. This is of particular relevance to minority groups such as the African American population, who often present with an aggressive TNBC with limited treatment options available.
Our collaborators at Johns Hopkins have laboratory data, suggesting that combining the histone deacetylase (HDAC) inhibitor entinostat with immune-checkpoint blockade (nivolumab and ipilimumab) led to eradication of breast tumors and long term cures. Research suggests that entinostat may alter the tumor environment by affecting the regulatory immune cells which can prevent immune-checkpoint agents from fighting cancer. This combination may thus be able to convert these traditionally “non-immunogenic” tumors into tumors which can respond to immune therapy.
We are thus conducting a phase I clinical trial of entinostat, nivolumab +/- ipilimumab in advanced solid tumors and patients with TNBC. We anticipate that the collection of blood and tumor specimens during the study will allow us to determine how these drugs are working in patients so we can develop future trials with the hope of significantly improving outcomes for patients with TNBC.
Immune targeted therapies, which stimulate the immune system to attach cancer have revolutionized cancer treatment strategies. These successes have offered new therapeutic avenues for cancer patients, especially for those with lung cancer. Despite the impressive clinical efficacy and duration of responses observed, the fraction of patients with durable responses remains in the order of 20% and there is therefore an unmet need to maximize efficacy of these treatments as well as identify the patients more likely to respond. We propose to use clinical samples from 2 novel clinical trials that combine immune targeted therapy with a different class of medicines, called epigenetic therapy. We have shown that epigenetic therapy may attract immune cells to the cancer site therefore “priming” an anti-tumor immune response. We propose to pinpoint the mechanisms that mediate response and resistance to these therapies by looking at the genetic make-up of cancer cells as well as by studying the tumor microenvironment. We believe our comprehensive, cutting-edge scientific approach linked with ongoing or soon to start clinical trials will result in immediate clinical intervention initiatives and is consistent with our mission to deliver improved treatments to patients with lung cancer.
Current therapies fail to cure 40% of breast cancer patients, who relapse and die from drug-resistant disease. Immune-based therapies work differently than drugs that destroy tumor cells directly by recruiting the patient’s own immune system to seek out and kill tumor cells. Immune-based therapies are not limited by drug resistance, are highly specific, and typically have few side effects. Importantly, they uniquely result in a durable therapeutic impact due to memory. Immune-based therapy includes vaccines and antibodies. Vaccines activate long-lasting T cells that kill existing cancers, and can remember to kill tumors should they arise again. Antibodies target proteins such as HER-2 on cancer cells, and immune cells bind these antibodies to kill tumors. HerceptinR is a HER-2-specific antibody that significantly improves the survival of patients with early and metastatic HER-2hi breast cancer.
Because tumors arise from the patient’s own tissues, the immune system sees them as “self” rather than as dangerous invaders (like an infection). A special type of regulatory T cell (Treg) keeps the immune system from recognizing “self”, and prevents tumor immunity. Low doses of the chemotherapy drug cyclophosphamide (CY) can reduce Tregs in breast cancer patients, sparing the good T cells needed to fight cancer. HER-2-specific antibodies can supercharge our cell-based vaccine by forming a bridge between HER-2 on the vaccine cells and host dendritic cells. Antibody-supercharged dendritic cells generate more killer/memory T cells of higher quality than dendritic cells alone. Our ongoing analysis of T cells from patients treated with CY, Herceptin and vaccine suggests that the T cells are of higher quality. We continue to test this strategy in patients with HER-2lo metastatic breast cancer, where Herceptin does not fight breast cancer directly. We have enrolled about 65% of the planned 60 patients. Our integrated clinical studies will identify the most active combination vaccine regimen to test for preventing relapse patients with early breast cancer, regardless of HER-2 expression level.
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