Targeted Cancer Immunotherapy

Overview of Cancer Immunotherapy

The immune system deals with cells and organisms that express foreign antigens by a process of antigen presentation to T cells then communication with B cells. This is followed by the production of cytotoxic T cells that can recognize antigens, and the production by differentiated B cells of antibodies that target those antigens. The system also has a memory process so that if an antigen is seen again, the immune response is mobilized even faster. T cells are capable of killing tumor cells. However, there are feedback mechanisms in many diseases, particularly cancer, that can turn off and/or repress the processes of antigen recognition and immune response.

Some experts have suggested that within 10 years, 60% of cancers will be treated with immunotherapy (Nature, Vol. 508, 3 April 2014). Immune responses can be induced and/or enhanced by vaccination using a single or handful of well-characterized tumor antigens. Injections of exogenously expanded cytotoxic T cells that recognize a single antigen on a patient’s cancer have been shown to eliminate metastatic disease in a subset of patients. However, cancers do not express a single antigen. Further, it is now known that most of these mutations are unique to that patient’s cancer; so it is not surprising that approaches that have involved immunization with only one or a few antigens, or injections of someone else’s cultured tumor cells have not been successful.

We believe that a better approach would involve a broader array of antigens and would utilize the patient’s own tumor, also known as autologous tumor. A number of those methods that have been tried have sought to draw antigens from an entire tumor mass. However, the cells of interest are the cancer stem cells or replicating cells, those with indefinite multiplicative capability. Only a few of those cells are present in the tumor mass, perhaps as few as 1/100,000 cells have this potential. Moreover, the tumor mass by definition includes a variety of other cells, such as immune cells, blood cells and other cells, some or many of which may inhibit or otherwise interfere with antigen recognition.

NeoStem’s Approach to Cancer Immunotherapy

NeoStem’s approach is different in two fundamental ways from other autologous therapies: (i) it presents to the patient’s immune system the entire spectrum of antigens from that patient’s own tumor and (ii) it separates out and re-administers just those cells from the patient’s tumor that are self-renewing, that is, those that can regenerate the cancer and cause metastatic spread against which an immune response is most needed. Those cells are pretreated with radiation and are connected to a dendritic cell to optimize presentation to the T cell.

Basic and clinical research have established that in some patients there is the ability to recognize tumor antigens, but as a result of their disease there are mechanisms that interfere with this process, while other patients have an existing immune recognition of tumor antigens, but their immune response is being suppressed. This is the basis for the new monoclonal antibody therapies such as anti-CTLA4, anti-PD-1, and anti-PD-L1 that are providing clinical benefit in the setting of metastatic melanoma. These so-called “checkpoint” inhibitors, i.e., drugs that block checkpoint proteins, work by either stimulating an existing immune response to tumor antigens, or liberating a repressed immune response to tumor antigens. However, their mechanisms of action rely on pre-existing recognition of tumor antigens by the immune system. NeoStem’s approach is different in that it is designed to induce or enhance recognition of all the tumor antigens expressed on the tumor’s self-renewing cells. In other words, the therapy’s intent is to increase the “target” specifically, its self-renewing stem cells.

Clinical Overview

The lead candidate in the program is the Company’s DC/TC (“dendritic cell/tumor cell”) product, a treatment for malignant melanoma. In a Phase 2 randomized clinical trial of subcutaneously injected DC/TC, DC/TC improved two year overall survival in patients with advanced melanoma (recurrent Stage III or Stage IV) to 72% compared to 31% for control patients treated with only their own tumor cells suspended in granulocyte macrophage colony stimulating factor (GM-CSF) (p=0.007). The toxicity profile was favorable with no grade IV and only one grade III (allergic reaction) event in the study. The allergic reaction was attributed to the granulocyte macrophage colony-stimulating factor (GMCSF), an FDA-approved immune stimulant used in the final drug formulation. There were no other significant toxicities seen in either an earlier single-arm Phase 2 trial or this randomized Phase 2 trial. Local injection site reactions, such as skin irritation and itching, did occur, but the symptoms dissipated within hours after the injection. There were no significant adverse effects on hematopoietic cells or renal function, liver function, or patient performance status. View Phase 2 trial results.

NeoStem’s immunotherapeutic approach is a platform technology that NeoStem believes could be expanded into other indications, such as hepatocellular carcinoma and other immune responsive tumor types.

Program Features

Our Immunotherapy Overcomes
Presents the entire spectrum of patient-specific   cancer initiating (stem) cells for the immune system to target Limited antigen targeting
Targets the cancer initiating (stem) cells that   express antigens associated with mutated cell lineages Tumor mutation/escape
Induces or enhances persistent T-cell immunity with activated dendritic cells Weak immune response
Uses autologous cancer antigen immune priming Toxicity


NeoStem - Cell Therapy Development - Clinical