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Lung metastases are a sign of widespread cancer with poor survival rate. Lung malignancies can originate from almost any cancer type spread via the blood stream. Most common lung metastases are from melanoma, breast cancer, bladder cancer, colon cancer, prostate cancer, neuroblastoma, and sarcoma. Living more than 5 years with lung metastases is uncommon, and surgical procedures are only effective with localized lung metastases. Lung metastasis are extremely frequent and resistant to regular treatment due to immunosuppressive regulatory sulfatide-reactive type II NKT cells.

Summary: 

The National Cancer Institute (NCI) is actively seeking potential licensees and/or co-development research collaboration partners interested in advancing oxynitidine derivatives as novel inhibitors of topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) for cancer treatment. These TOPI and TDP1 inhibitors, when administered together, demonstrate enhanced anti-tumor efficacy.

Description of Technology: 

Triple negative (progesterone receptor (PR)-, estrogen receptor (ER)-, human epidermal growth receptor 2 (HER2)-) breast cancer (TNBC) is an aggressive subtype that affects 15-20% of the 1.7 million cases of breast cancer occurring annually.  Currently, standard treatments of TNBC include cytotoxic chemotherapies, surgery, and radiation. However, TNBC readily becomes resistant to chemotherapy, and those with TNBC are more likely to have a recurrence or die within five years compared to those with other breast cancer types.

T cells with T cell receptors (TCRs) for cancer-specific antigens are used for adoptive cell therapy (ACT), wherein a patient’s T cells are redirected against their own cancer. However, these isolated T cells may require further ex vivo manipulation to enhance their anti-tumor activity. The ex vivo manipulation of these T cells, or the selection of less functionally inert T cells, and genetic insertion of tumor specific TCRs may circumvent these limitations.

Adoptive cell transfer (ACT) uses tumor infiltrating lymphocytes (TILs) that recognize unique antigens expressed by cancer cells (“neoantigens”). Neoantigen specific TIL administration in patients has resulted in long term regression of certain metastatic cancers. However, one of the challenges of ACT and engineered T cell receptor (TCR) therapies more broadly, is the identification and isolation of these mutation specific TILs and TCRs. Only a fraction of TILs in a given patient is known to be tumor reactive, while the majority are not useful for cell therapy.

Adoptive cell transfer (ACT) uses tumor infiltrating lymphocytes (TILs) that recognize antigens expressed by cancer cells (neoantigens). Neoantigen specific TIL administration in patients has resulted in long-term regression of certain metastatic cancers. However, current procedures for TIL therapy are highly invasive, labor-intensive, and time consuming. The success of these procedures is limited and differs between patients and histologies.

CD20 is a protein expressed by wide ranges of lymphoid malignancies originating from B cells but not by indispensable normal tissues, making it an attractive target for therapies such as T-cell receptor (TCR) therapy. Current anti-CD20 therapeutics face a number of limitations. The most important limitation to current anti-CD20 therapies include cancer cells becoming resistant to the therapy.

Recombinant Immunotoxins (RITs) are chimeric molecules composed of an antigen binding domain and toxin. The antigen binding domain component targets the cancer cell and delivers the toxin component to the cell. However, the efficacy of RITs is limited by their short half-life once they are in the patient. To address this problem, investigators at the National Cancer Institute (NCI) increased the half-life of RITs using polyethylene glycol (PEG).

Mesothelin (MSLN) is an antigen highly expressed in several human cancers including mesotheliomas, ovarian cancers and pancreatic cancers. As such, human MSLN (hMSLN) is a target for many anti-cancer drugs. Most therapeutics targeting hMSLN do not recognize the mouse isoform of MSLN (mMSLN) and therefore cannot be tested in mouse cancer models. 

Pancreatic ductal adenocarcinoma (PDA) accounts for more than 90% of pancreatic cancer cases, and it is one of the most aggressive malignancies with a 5-year survival rate of 6%. The high mortality rate caused by PDA is primarily from the lack of early diagnosis – it is often asymptomatic in early stages – and a poor response to conventional chemotherapy and radiotherapy. One of the major immune cell types present in the PDA microenvironment is a subset of macrophages commonly termed tumor-associated macrophages (TAM).