Tune & Track –
AffyImmune’s Platform for Attacking Solid Tumors
AffyImmune is developing the next generation of cellular immunotherapies to enhance the ability of a patient’s own immune system to detect and eliminate tumor cells.
Through affinity-tuning and in vivo tracking, AffyImmune’s CAR T cells have enhanced tumor killing while avoiding damage to normal cells and tissues.
Cancer Immunotherapy
Our immune system protects our bodies from foreign pathogens and eliminates diseased and damaged cells. This process is dependent on recognition of antigens expressed on the surface of abnormal cells, which is an integral part of the immune system’s ability to discriminate between foreign and host cells.
In the case of cancer, the immune system’s ability to detect such tumor associated antigens on cancer cells is largely ineffective. Tumor cells are able to establish a microenvironment inhibitory to immune cells and employ a number of other mechanisms to escape detection by the immune system, leading to continued tumor growth and disease progression.
Recent innovations in cancer therapy have led to the development of treatments called immunotherapies. Immunotherapies do not attack the cancer directly, but rather improve the ability of the immune system to both identify cancer cells and to overcome the tumors’ defense mechanisms. No other type of therapy offers the potential to provide robust and long-lasting anti-tumor activity as an effectively activated immune system.
CAR T cell Therapy
CAR T cell therapy is a cell-based immunotherapy where a patient’s own T cells are modified to express chimeric antigen receptors (CARs). CARs are genetically engineered molecules designed to help T cells seek and destroy tumor cells by allowing them to recognize specific antigens on the tumor cell-surface that are otherwise invisible to them.
CARs are comprised of an extracellular domain that targets a tumor associated antigen, a spacer and transmembrane domain, as well as intracellular domains required for activation of the CAR T cell, leading to tumor eradication and T cell proliferation.
CAR T cell treatment requires the harvesting of a patient’s white blood cells through a process called leukapheresis. T cells are then selected, genetically engineered to express CARs targeting the tumor and grown up in culture. These engineered T cells, capable of recognizing tumor cells, are then infused back into the patient.
CAR T cell therapies have been successfully tested in the clinic and approved for the treatment of blood cancers.
TECHNOLOGY
Challenges to CAR T Cell Therapy
CAR T cell therapy is one of the most promising therapies for fighting cancer to emerge in the last several decades, having shown its potential in the treatment of blood cancers. Yet CAR T cell therapies have largely been ineffective in treating solid tumors, which account for 90% of all cancer fatalities.
The utility of CAR T cells in eliminating cancer cells is dependent on arming them to recognize tumor associated antigens not expressed on healthy cells. Yet, particularly with solid tumors, there are very few tumor-associated antigens exclusively expressed on cancer cells, making selective targeting difficult. Low level expression of tumor associated antigens on normal cells can lead to killing of normal cells by CAR T cells during therapy, leading to significant side effects and toxicity.
AffyImmune is developing technologies to expand the utility and improve the safety of CAR T cell therapies for solid tumors by addressing all of these limitations. Specifically, the company is using its tuning technology to design CAR T cells that can distinguish tumor cells from normal ones expressing the same antigen at lower levels. This approach promises to increase the therapeutic window, leading to effective killing of tumor cells with greatly reduced toxicity and increased tolerability.
Affinity-Tuned CARs
While the majority of CAR T cell approaches to date have utilized CARs having very high affinity for their target, mounting evidence suggests that this may not be the most effective approach for several reasons. High-affinity CARs will also bind targets expressed at lower levels on normal tissues, leading to unwanted toxicity, and may also become exhausted through prolonged activation. Lower-affinity CARs, however, effectively bind to tumor cells having higher levels of antigen expression while avoiding normal cells with basal levels of antigen. Furthermore, binding of lower affinity CARs results in activation of CAR T cells in a manner more similar to the natural activation observed in non-engineered T cells. This more physiological activation leads to better serial tumor cell killing, clonal expansion and long-term persistence to result in greater effectiveness.
AffyImmune’s technology enables precise affinity-tuning of CAR T cells to select those targeting overexpressed but non-unique tumor associated antigens, thereby avoiding toxicity to normal cells expressing lower levels of the target. Our studies in preclinical animal models of various solid human tumors show that our affinity-tuned CAR T cells produce robust and enduring tumor eradication with no toxicity.
Low Affinity CAR T Cells
High Affinity CAR T Cells
Real-Time CAR T Cell Monitoring
CAR T cell therapies can sometimes lead to severe toxicities, primarily due to a condition called cytokine release syndrome (CRS). CRS is caused by a large and rapid release of cytokines into the blood by the activated CAR T cells themselves, sometimes triggered by extensive killing of tumor cells. Although treatable, careful monitoring of the patient is required in order to detect CRS and other potentially severe toxicities at their earliest onset.
AffyImmune has developed a tracking system that is engineered into CAR T cells to monitor, in real-time, the distribution and activity of CAR T cells within the body after administration to the patient. This unique tracking system provides information on the functional status of the cells, showing whether cells are multiplying at the site of cancer or in normal tissues. This helps predict potential CRS or other severe toxicities and prepare for treatment.
AffyImmune’s proprietary CAR T Cell tracking technology is based on the expression of a marker, somatostatin receptor 2 (SSTR2), on our engineered CAR T cells, which can then be detected with the clinically approved PET/CT imaging probe 68Ga-DOTATATE. In the future, SSTR2 has the potential to be used as a safety switch and activity modulator to further increase safety and efficacy of our CAR T therapies.
TARGETS
ICAM-1
Intracellular adhesion molecule 1 (ICAM-1) has been shown to be highly expressed on cancer cells and is highly correlated with an increase in the metastatic potential of solid tumors. ICAM-1 expression is also highly inducible. Both radiation and T cell mediated cytotoxicity increase the expression of ICAM-1 in surrounding cancer cells. This makes ICAM-1 a uniquely attractive target for CAR T cell therapy with broad applicability. For these reasons, AffyImmune has selected an affinity-tuned CAR T cell targeting ICAM-1 as its lead clinical development product (AIC100).
INDICATIONS
Our lead product, AIC100, is currently being developed to treat anaplastic and relapsed/refractory thyroid cancer, gastric cancer, and triple negative breast cancer.
Anaplastic and Refractory Thyroid Cancer
Thyroid cancer is caused by the abnormal growth of cells in the thyroid gland tissues and is the fifth most common malignancy in women. Although most thyroid cancers are curable, prognosis is very poor for anaplastic and refractory thyroid cancers (ATRC). Anaplastic thyroid cancer is a rare, aggressive, and highly metastatic thyroid cancer that makes up less than 2% of all thyroid cancers. The relapse rate of other thyroid cancers is ~20%, with up to 30% of relapsing tumors becoming refractory to all currently available therapies. For ARTC, few effective therapies are available, and life expectancy is less than a year. ICAM-1 overexpression is observed consistently in all these more advanced thyroid cancers, and high expression of ICAM-1 has been associated with lower survival rates in these patients. AffyImmune has chosen ARTC as the initial cancer for treatment with AIC100 and has received both Orphan Drug and Fast Track Designation.
Gastric Cancer
Gastric cancer is a disease where malignant cells form in the lining of the stomach. Gastric cancer is the fifth most commonly diagnosed cancer and third leading cause of cancer death worldwide, with a higher incidence in men. Since early stages of gastric cancer are usually asymptomatic, patients are often diagnosed only at later stages of the disease. This is one of the primary reasons for the low survival rates and poor prognosis. Elevated ICAM-1 expression is highly correlated with metastasis, recurrence, and low survival in gastric cancer patients.
Publications
- Yang, Y. et al. Bispecific CAR T cells against EpCAM and inducible ICAM-1 overcome antigen heterogeneity and generate superior anti-tumor response. Cancer Immunol. Res. (in press)
- Jung, M. et al. Chimeric antigen receptor T cell therapy targeting ICAM-1 in gastric cancer. Mol Ther Oncolytics 2020 18, 587 (2020)
- Vedvyas, Y. et al. Manufacturing and preclinical validation of CAR T cells targeting ICAM-1 for advanced thyroid cancer therapy. Scientific reports 9, 10634 (2019).
- Min, I.M., et al. CAR T Therapy Targeting ICAM-1 Eliminates Advanced Human Thyroid Tumors. Clin Cancer Res 23, 7569-7583 (2017).
- Park, S., et al. Micromolar affinity CAR T cells to ICAM-1 achieves rapid tumor elimination while avoiding systemic toxicity. Scientific reports 7, 14366 (2017).
- Vedvyas, Y., et al. Longitudinal PET imaging demonstrates biphasic CAR T cell responses in survivors. JCI Insight 1, e90064 (2016).