Evaluation of CAR T Cell Therapy

CAR T Cell Therapy

It is common knowledge that cancer has a major impact on societies around the world. In 2018, it was estimated that a total of 1.7 million new cases of cancer were diagnosed in the United States alone (1). While it seems like the types of cancers that can develop are endless, the most common cancers include: breast, lung, colon, prostate, melanoma and various lymphomas and leukemias (1). With consistently increasing incidence and mortality rates, identifying effective cancer treatments and therapies is key. One of the newest and potentially life changing therapies being investigated is the use of chimeric antigen receptor T cells (CAR T cells).

CAR T therapy relies on the patient’s own immune system to fight off the cancer cells and tumors and is therefore considered an adoptive cellular therapy (2). Within the clinic, blood is taken from the patient and processed to isolate their T cells (3). The isolated T cells can then be outsourced to labs or manufacturing facilities where an inactive virus, typically a lenti- or retro-virus, will be used to insert specific genes into the patient’s T cells, resulting in the production of chimeric receptors on the T cell surfaces specific for tumor antigens. These modified T cells, now known as CAR T cells, are selected for and allowed to proliferate before being reintroduced into the patient after they undergo lymphodepletion (3). If successful, infusion of the CAR T cells will result in the detection of tumor antigens and the destruction of cancerous lymphocytes.

CAR T cells have evolved greatly since they were first developed as there are now four generations (4). Typically, the first generation involves a single structure from the CD-3 zeta chain (FcεRIγ), which is the primary endogenous T cell signal transmitter (4). Unfortunately, generation one CAR Ts do not produce enough IL-2 on their own to kill tumor cells, so patients must receive exogenous IL-2 (4). Second generation CAR Ts utilize dual signaling and three different receptor types: T cell antigen receptors, cytokine receptors and co-stimulatory receptors (4). Second generation CAR Ts rely on co-stimulatory receptors such as CD28/B7, or CD137 to help increase IL-2 production and consequently, tumor cell killing (4). Third generation CAR Ts combine multiple signaling domains including CD3 zeta-CD28-OX40 or CD3 zeta-CD28-41BB, again allowing for an increase in cytokine production and advanced tumor cell killing (4). Third generation CAR Ts have only been tested in a small number of cases and need to be investigated further to understand their safety implications (4). Lastly, fourth generation CAR Ts are modified second generation cells (4). They were generated by adding IL-12 to the second-generation constructs and are used for T cell redirected universal cytokine mediated killing (TRUCKs) (4). Rather than using T cells to directly kill tumor cells, TRUCKs augment T cell activation and attract innate immune cells to target cancerous cells (4).

As of 2019, a variety of CAR T cell therapies have been approved, most of them focusing on CD19 as the target. CD19 is a surface marker for B cells in Acute Lymphoid Leukemia as well as a marker for all other B cell malignancies since it is expressed throughout B cell development (2). Clinical results from studies examining CD19 targeted CAR T cells in adult B cell acute lymphoid leukemia (ALL) have been promising; demonstrating consistently high anti-tumor effects (5). Adults and children treated with Kymriah, an FDA approved CD19 CAR T cell, demonstrated robust responses without a secondary therapy (6). After 24-months, the relapse-free survival rate for patients was 62% with unreached median durations of remission and medial overall survival rates, suggesting a sustained and effective treatment for patients with B cell ALL (6).

While the benefits of CAR T therapy are obvious, like all therapies and treatments, side effects and toxicities are possible. One of the most dangerous toxicities that is possible with CAR T therapy is a cytokine storm (3). A cytokine storm results from rapid immune activation induced by the CAR T cells; large amounts of pro-inflammatory cytokines are released and over-activate the immune system (3). Early symptoms of a cytokine storms include fever and fatigue, but can progress to vasodilatory shock, hypoxia and even death if not treated (3). The potential for on-target, off tumor toxicity also exists. Although it is important to choose the correct target for CAR T therapy, often it is difficult to find the ‘perfect’ target antigen; as a result, CAR T cells may target non-tumor cells that also express the same marker, resulting in tissue damage (3). Due to the it’s expression throughout the B cell life cycle, targeting CD19 often results in B cell aplasia (3). While low numbers or the absence of B cells is typically not desirable, B cell aplasia is often used as an indicator of successful CD19-specific CAR T therapy (3).

Although CD19 CAR T cell therapies have been approved by the FDA, clinical trials are still occurring to help optimize treatments as well as gain an understanding on why relapses may occur. A future phase I clinical trial in China is scheduled to examine the use of CD19 CAR T cells in patients with relapsed or refractory B cell ALL as well as assess their quality of life post-treatment (7). The primary outcome from this study is to observe the percentage of patients that achieve complete or partial remission, while the secondary objectives are to measure the amount of CAR T cells present on a monthly basis for two years post-infusion (7). This is quite a broad study, accepting volunteers between the ages of 3-70 and of all sexes (7). Completion of this study is estimated for December 31, 2019 (10).

While most of the clinical focus is on the use of CD19 CAR T cells for ALL treatment, other studies are currently active and testing the use of CAR T cells to treat a myriad of other types of cancers. A Washington based Children’s hospital is recruiting for an upcoming phase I trial in which the safety of HER2-specific CAR T cells and administration techniques will be observed and determined (8). It is the study director’s hope that the HER2-specific CAR T cells can be administered through an indwelling CNS catheter, allowing for direct T cell/tumor interaction to help treat CNS and brain related cancers (8). The cornucopia of clinical trials that exists with the goal of developing novel CAR T therapies is exciting and shows the therapeutic benefit associated with this treatment. Additional targets that are being investigated include: EGFR for non-small cell lung cancer and carcinomas, IL-13Ra2 for glioma and FR-a for ovarian cancer, as well as many others (9).

The future of CAR T therapy looks promising as new targets are being investigated and clinical trials are on-going. With the inability to completely prevent the formation of cancer, effective treatment options are a necessity and CAR T therapies bridge the gap between previous immuno-oncology agents. The generation of chimeric antigen receptors and use of a patient’s own immune cells is invaluable as this form of treatment provides a successful and robust alternative to chemotherapy. Although CAR T therapy is still new, and toxicities still exits, risk/benefit analysis shows that it is a powerful treatment option for patients with a variety of cancers.

References:

1. National Cancer Institute, (2018), Cancer statistics, National Cancer Institute,
   
   https://www.cancer.gov/about-cancer/understanding/statistics
   
2. Maude et. al, (2015), CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia, Blood, 125(26), pp: 4017-4023.
3. Leukemia & Lymphoma Society, (n.d), Chimeric antigen receptor (CAR) T cell therapy, Leukemia & Lymphoma Society,
   
   https://www.lls.org/treatment/types-of-treatment/immunotherapy/chimeric-antigen-receptor-car-t-cell-therapy
   
4. Zhang, C., Liu, J., Zhong, J. F., & Zhang, X. (2017). Engineering CAR-T cells.
   
   Biomarker research
   
   ,
   
   5
   
   , 22. doi:10.1186/s40364-017-0102-y
5. Part et. al, (2016), CD19- targeted CAR T-cell therapeutics for hematologic malignancies: Interpreting clinical outcomes to date
6. Novartis, (2018), Novartis announces longer-term analyses from pivotal Kymriah trials that showed durable responses are maintained in patients with advanced blood cancers, Novartis,
   
   https://www.novartis.com/news/media-releases/novartis-announces-longer-term-analyses-from-pivotal-kymriah-trials-showed-durable-responses-are-maintained-patients-advanced-blood-cancers
   
7. Xu, Z., (2018), CD19-CAR T cells in patients with R/R B-ALL, Clinicaltrials.gov,
   
   https://clinicaltrials.gov/ct2/show/NCT03574168?term=CD19+CAR+T&recrs=ad&rank=5
   
8. Vitanza, N., (2019), HER2-specific CAR T cell locoregional immunotherapy for HER2-positive recurrent/refractory pediatric CNS tumors, Clinicaltrials.gov,
   
   https://clinicaltrials.gov/ct2/show/NCT03500991?term=CAR+T+cells&rank=8
   
9. Zhang, C., Kasi, A., (2019), Chimeric antigen receptor (CAR) T cell therapy, StarPearls, StatPearls publishing, Treasure Island, FL,
   
   https://www.ncbi.nlm.nih.gov/books/NBK537294/
   

CAR T Cell Therapy

It is common knowledge that cancer has a major impact on societies around the world. In 2018, it was estimated that a total of 1.7 million new cases of cancer were diagnosed in the United States alone (1). While it seems like the types of cancers that can develop are endless, the most common cancers include: breast, lung, colon, prostate, melanoma and various lymphomas and leukemias (1). With consistently increasing incidence and mortality rates, identifying effective cancer treatments and therapies is key. One of the newest and potentially life changing therapies being investigated is the use of chimeric antigen receptor T cells (CAR T cells).

CAR T therapy relies on the patient’s own immune system to fight off the cancer cells and tumors and is therefore considered an adoptive cellular therapy (2). Within the clinic, blood is taken from the patient and processed to isolate their T cells (3). The isolated T cells can then be outsourced to labs or manufacturing facilities where an inactive virus, typically a lenti- or retro-virus, will be used to insert specific genes into the patient’s T cells, resulting in the production of chimeric receptors on the T cell surfaces specific for tumor antigens. These modified T cells, now known as CAR T cells, are selected for and allowed to proliferate before being reintroduced into the patient after they undergo lymphodepletion (3). If successful, infusion of the CAR T cells will result in the detection of tumor antigens and the destruction of cancerous lymphocytes.

CAR T cells have evolved greatly since they were first developed as there are now four generations (4). Typically, the first generation involves a single structure from the CD-3 zeta chain (FcεRIγ), which is the primary endogenous T cell signal transmitter (4). Unfortunately, generation one CAR Ts do not produce enough IL-2 on their own to kill tumor cells, so patients must receive exogenous IL-2 (4). Second generation CAR Ts utilize dual signaling and three different receptor types: T cell antigen receptors, cytokine receptors and co-stimulatory receptors (4). Second generation CAR Ts rely on co-stimulatory receptors such as CD28/B7, or CD137 to help increase IL-2 production and consequently, tumor cell killing (4). Third generation CAR Ts combine multiple signaling domains including CD3 zeta-CD28-OX40 or CD3 zeta-CD28-41BB, again allowing for an increase in cytokine production and advanced tumor cell killing (4). Third generation CAR Ts have only been tested in a small number of cases and need to be investigated further to understand their safety implications (4). Lastly, fourth generation CAR Ts are modified second generation cells (4). They were generated by adding IL-12 to the second-generation constructs and are used for T cell redirected universal cytokine mediated killing (TRUCKs) (4). Rather than using T cells to directly kill tumor cells, TRUCKs augment T cell activation and attract innate immune cells to target cancerous cells (4).

As of 2019, a variety of CAR T cell therapies have been approved, most of them focusing on CD19 as the target. CD19 is a surface marker for B cells in Acute Lymphoid Leukemia as well as a marker for all other B cell malignancies since it is expressed throughout B cell development (2). Clinical results from studies examining CD19 targeted CAR T cells in adult B cell acute lymphoid leukemia (ALL) have been promising; demonstrating consistently high anti-tumor effects (5). Adults and children treated with Kymriah, an FDA approved CD19 CAR T cell, demonstrated robust responses without a secondary therapy (6). After 24-months, the relapse-free survival rate for patients was 62% with unreached median durations of remission and medial overall survival rates, suggesting a sustained and effective treatment for patients with B cell ALL (6).

While the benefits of CAR T therapy are obvious, like all therapies and treatments, side effects and toxicities are possible. One of the most dangerous toxicities that is possible with CAR T therapy is a cytokine storm (3). A cytokine storm results from rapid immune activation induced by the CAR T cells; large amounts of pro-inflammatory cytokines are released and over-activate the immune system (3). Early symptoms of a cytokine storms include fever and fatigue, but can progress to vasodilatory shock, hypoxia and even death if not treated (3). The potential for on-target, off tumor toxicity also exists. Although it is important to choose the correct target for CAR T therapy, often it is difficult to find the ‘perfect’ target antigen; as a result, CAR T cells may target non-tumor cells that also express the same marker, resulting in tissue damage (3). Due to the it’s expression throughout the B cell life cycle, targeting CD19 often results in B cell aplasia (3). While low numbers or the absence of B cells is typically not desirable, B cell aplasia is often used as an indicator of successful CD19-specific CAR T therapy (3).

Although CD19 CAR T cell therapies have been approved by the FDA, clinical trials are still occurring to help optimize treatments as well as gain an understanding on why relapses may occur. A future phase I clinical trial in China is scheduled to examine the use of CD19 CAR T cells in patients with relapsed or refractory B cell ALL as well as assess their quality of life post-treatment (7). The primary outcome from this study is to observe the percentage of patients that achieve complete or partial remission, while the secondary objectives are to measure the amount of CAR T cells present on a monthly basis for two years post-infusion (7). This is quite a broad study, accepting volunteers between the ages of 3-70 and of all sexes (7). Completion of this study is estimated for December 31, 2019 (10).

While most of the clinical focus is on the use of CD19 CAR T cells for ALL treatment, other studies are currently active and testing the use of CAR T cells to treat a myriad of other types of cancers. A Washington based Children’s hospital is recruiting for an upcoming phase I trial in which the safety of HER2-specific CAR T cells and administration techniques will be observed and determined (8). It is the study director’s hope that the HER2-specific CAR T cells can be administered through an indwelling CNS catheter, allowing for direct T cell/tumor interaction to help treat CNS and brain related cancers (8). The cornucopia of clinical trials that exists with the goal of developing novel CAR T therapies is exciting and shows the therapeutic benefit associated with this treatment. Additional targets that are being investigated include: EGFR for non-small cell lung cancer and carcinomas, IL-13Ra2 for glioma and FR-a for ovarian cancer, as well as many others (9).

The future of CAR T therapy looks promising as new targets are being investigated and clinical trials are on-going. With the inability to completely prevent the formation of cancer, effective treatment options are a necessity and CAR T therapies bridge the gap between previous immuno-oncology agents. The generation of chimeric antigen receptors and use of a patient’s own immune cells is invaluable as this form of treatment provides a successful and robust alternative to chemotherapy. Although CAR T therapy is still new, and toxicities still exits, risk/benefit analysis shows that it is a powerful treatment option for patients with a variety of cancers.

References:

1. National Cancer Institute, (2018), Cancer statistics, National Cancer Institute,
   
   https://www.cancer.gov/about-cancer/understanding/statistics
   
2. Maude et. al, (2015), CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia, Blood, 125(26), pp: 4017-4023.
3. Leukemia & Lymphoma Society, (n.d), Chimeric antigen receptor (CAR) T cell therapy, Leukemia & Lymphoma Society,
   
   https://www.lls.org/treatment/types-of-treatment/immunotherapy/chimeric-antigen-receptor-car-t-cell-therapy
   
4. Zhang, C., Liu, J., Zhong, J. F., & Zhang, X. (2017). Engineering CAR-T cells.
   
   Biomarker research
   
   ,
   
   5
   
   , 22. doi:10.1186/s40364-017-0102-y
5. Part et. al, (2016), CD19- targeted CAR T-cell therapeutics for hematologic malignancies: Interpreting clinical outcomes to date
6. Novartis, (2018), Novartis announces longer-term analyses from pivotal Kymriah trials that showed durable responses are maintained in patients with advanced blood cancers, Novartis,
   
   https://www.novartis.com/news/media-releases/novartis-announces-longer-term-analyses-from-pivotal-kymriah-trials-showed-durable-responses-are-maintained-patients-advanced-blood-cancers
   
7. Xu, Z., (2018), CD19-CAR T cells in patients with R/R B-ALL, Clinicaltrials.gov,
   
   https://clinicaltrials.gov/ct2/show/NCT03574168?term=CD19+CAR+T&recrs=ad&rank=5
   
8. Vitanza, N., (2019), HER2-specific CAR T cell locoregional immunotherapy for HER2-positive recurrent/refractory pediatric CNS tumors, Clinicaltrials.gov,
   
   https://clinicaltrials.gov/ct2/show/NCT03500991?term=CAR+T+cells&rank=8
   
9. Zhang, C., Kasi, A., (2019), Chimeric antigen receptor (CAR) T cell therapy, StarPearls, StatPearls publishing, Treasure Island, FL,
   
   https://www.ncbi.nlm.nih.gov/books/NBK537294/