Leverage Your Natural Anti-Cancer Defenses to Attain Long-Term Immunity
Evading the immune system is necessary for cancer’s survival. An important mechanism through which cancer suppresses immunity involves the inhibitory function of signal regulatory protein alpha (SIRPɑ) on macrophages, a predominant immune cell in the tumor microenvironment. Several key discoveries revealed that SIRPɑ not only suppresses the anti-cancer activity of macrophages but also strongly promotes their cancer-supporting capacity. These discoveries laid the foundation to provide a non-genetic approach to reprogramming macrophages – PhagoAct™ – that removes SIRPɑ from macrophages and simultaneously reprograms them to promote an anti-cancer response.
Key Attributes and Differentiating Elements of SIRPant-M™
- Produces polyclonal tumor neo-antigen-directed CD8+ T cell responses
- Drives polyclonal tumor neo-antigen-directed antibody responses
- Targets both the primary tumor lesion and metastases
- Results in long-lived immunity that prevents recurrence
- Short manufacturing time (significantly reduced when compared to CAR-T)
- Requires no genetic manipulation of patient’s cells
The Process – SIRPant-M™
The SIRPant-M™ approach takes patients’ own immune cells from peripheral blood and transforms them into highly aggressive anti-cancer macrophages that display a remarkable capacity to directly blunt tumor growth and drive an attack on metastatic lesions.
Similar to drafting and training soldiers for war, SIRPant-M™ mobilizes cells to fight cancer, in much the same way as they do in healthy individuals day-in and day-out.
This process involves:
1. Taking Patient Cells From Peripheral Blood
2. Differentiating Peripheral Blood Cells Into Macrophages
3. Training The Macrophages
4. Providing Them Back To The Patient
5. Directly Attacking Cancer
6. Establishing Immune Memory
SIRPANT-M™ has several key attributes and differentiating elements that enable macrophages to achieve robust control of advanced, hard-to-treat cancers.
Cancer-Agnostic Phagocytosis
PhagoAct™ alters the expression of several proteins involved in macrophage phagocytosis in a manner that enables SIRPANT-M™ to recognize and uptake cancerous cells within treated tumors without the need of cancer-directed antibodies or chimeric receptors. This differentiating factor endows SIRPANT-M™ with largely unrestricted potential in treating a range of oncologic indications.
Immunogenic Antigen Presentation
SIRPANT-M™ is optimized to potently activate polyclonal cancer-specific cytotoxic T cells that subsequently expand, circulate, infiltrate, and eliminate cancerous lesions throughout the body. This enhanced capacity to bridge innate and adaptive immunity is highly synergistic with other immuno-stimulatory therapeutic modalities including radiotherapy and immune checkpoint inhibitors to achieve elimination of otherwise treatment-refractory tumors.
Immune Cell Reprogramming
SIRPANT-M™ is proficiently engineered to induce a pro-inflammatory phenotypic switch in proximal and distal immunosuppressive immune cells (e.g., myeloid-derived suppressors cells and CD4 T regulatory cells), leading to a paradigm shift within tumor microenvironments that instead favors the elimination of cancer cells.
Established Anamnestic Response
SIRPANT-M™ not only achieves durable control of treated tumors and accompanying metastases but also confers persistent cellular and humoral (antibody) immunity that has been shown to preclude relapse of the same or different cancers.
SIRPant-M™ vs other cell- and antibody-based therapies
Current best-in-class cellular immunotherapies, such as CAR-T cells, employ targeted effector cells of the immune system (T cells) to attack cancer. These cells typically target a single tumor-associated antigen to mount the immune response. SIRPant-M™ is different. SIRPant-M™ macrophages promote a response by a variety of different T cells—T cells that are tumor neo-antigen-specific and are already present in the patient but have been “switched off” by the tumor itself. In pre-clinical animal models, this leads to a polyclonal CD8+ T cell response that hits the tumor from multiple different angles and leads to direct tumor killing. In addition, this approach promotes CD4+ T cell responses that elaborate a B cell-driven polyclonal antibody response, this time hitting the cancer with antibodies from multiple different angles. This results in an immune response that attacks all of the tumors in a patient (including metastases) and provides long-lived immunity to curtail cancer recurrence.
Macrophages are just one of several types of myeloid immune cells. Dendritic cells (DCs) are renowned for their ability to initiate primary immune responses (responses against agents the body has never seen before) and several products have entered clinical testing to leverage this unique capacity of DCs. However, it is now appreciated that many patients already have inside of them T cells that can recognize and target a tumor, but these cells have been turned off. This is where SIRPant-M™ macrophages shine. Macrophages in general are very potent drivers of secondary immune responses and SIRPant-M™ macrophages are capable of doing so even in the face of a tumor that is fighting to prevent such a response. Because of their simplicity and their potency, macrophages can play a key role in flipping the switch back to promote effective anti-tumor immunity. And SIRPant-M™ macrophages do this without the need to pre-identify tumor neo-antigens and without the need for targeting singular tumor-associated antigens.
The development of Rituximab, a monoclonal antibody that specifically targets a tumor-associated antigen (CD20), resulted in the first FDA-approved antibody for the treatment of cancer. This was a pivotal step forward for the field of immunotherapy. In this context, mobilizing the immune system against an antigen associated with Non-Hodgkin’s Lymphoma results in an immune response that is quite effective for the treatment of patients. SIRPant-M™ builds on these seminal findings in immunotherapy. Rather than administering a single antibody itself, SIRPant-M™ propels the body’s own antibody producing cells (B cells) to generate antibodies against many tumor neo-antigens (not just tumor-associated antigens), thereby producing antibodies that specifically and polyclonally targeting cancer cells. With this comes long-lived immunity, which again is self-sustained from the patient’s own cells.
vs lymphocyte cell-based therapies
Current best-in-class cellular immunotherapies, such as CAR-T cells, employ targeted effector cells of the immune system (T cells) to attack cancer. These cells typically target a single tumor-associated antigen to mount the immune response. SIRPant-M™ is different. SIRPant-M™ macrophages promote a response by a variety of different T cells—T cells that are tumor neo-antigen-specific and are already present in the patient but have been “switched off” by the tumor itself. In pre-clinical animal models, this leads to a polyclonal CD8+ T cell response that hits the tumor from multiple different angles and leads to direct tumor killing. In addition, this approach promotes CD4+ T cell responses that elaborate a B cell-driven polyclonal antibody response, this time hitting the cancer with antibodies from multiple different angles. This results in an immune response that attacks all of the tumors in a patient (including metastases) and provides long-lived immunity to curtail cancer recurrence.
vs myeloid cell-based therapies
Macrophages are just one of several types of myeloid immune cells. Dendritic cells (DCs) are renowned for their ability to initiate primary immune responses (responses against agents the body has never seen before) and several products have entered clinical testing to leverage this unique capacity of DCs. However, it is now appreciated that many patients already have inside of them T cells that can recognize and target a tumor, but these cells have been turned off. This is where SIRPant-M™ macrophages shine. Macrophages in general are very potent drivers of secondary immune responses and SIRPant-M™ macrophages are capable of doing so even in the face of a tumor that is fighting to prevent such a response. Because of their simplicity and their potency, macrophages can play a key role in flipping the switch back to promote effective anti-tumor immunity. And SIRPant-M™ macrophages do this without the need to pre-identify tumor neo-antigens and without the need for targeting singular tumor-associated antigens.
vs antibody-based immunotherapies
The development of Rituximab, a monoclonal antibody that specifically targets a tumor-associated antigen (CD20), resulted in the first FDA-approved antibody for the treatment of cancer. This was a pivotal step forward for the field of immunotherapy. In this context, mobilizing the immune system against an antigen associated with Non-Hodgkin’s Lymphoma results in an immune response that is quite effective for the treatment of patients. SIRPant-M™ builds on these seminal findings in immunotherapy. Rather than administering a single antibody itself, SIRPant-M™ causes the patient’s own antibody producing cells (B cells) to generate antibodies against many tumor neo-antigens (not just tumor-associated antigens), thereby producing antibodies that specifically and polyclonally targeting cancer cells. With this comes long-lived immunity, which again is self-sustained from the patient’s own cells.