Chimeric antigen receptor T-cell (CAR-T) therapy is one of the most exciting developments in the oncology space. This immunotherapy is driving durable responses in patients with previously unresponsive cancers, and it’s changing the way researchers, clinicians and patients think about cancer treatment. In January, 2018, ASCO declared CAR-T therapy the Advance of the Year, and hundreds of clinical trials are underway globally to identify new ways to leverage this immunotherapy for a broader patient population.
However, the proven efficacy of CAR-T cell therapy is tempered by challenges. The only approved CAR-T therapies to date are for patients with blood-born cancers, including adult B-Cell non-Hodgkin’s lymphoma or childhood acute lymphoblastic leukemia (ALL) for whom conventional treatments have repeatedly failed. But current research is pushing the boundaries of what this treatment can deliver.
Long term follow-up of CAR-T trials show patients with lower disease burden have responded better and experience fewer adverse events, suggesting the potential to use CAR-T therapy as an earlier line of treatment. Yet some patients don’t respond at all, others respond then relapse, and a small but significant group experience rare but potentially fatal side effects, including neurotoxicity and cytokine-release syndrome, which leads to high fevers, joint pain, and a dramatic drop in blood pressure. In addition, the cost and complexity of CAR-T cell therapy has slowed the uptake of marketed therapies. Many of these challenges are being tackled by new biotech companies and academic researchers who bring a variety of innovative solutions and novel CAR-T platforms to the clinic.
Driving CAR-T Response in Solid Tumors
The early success of CAR-T therapies in hematologic cancers is driving many researchers to consider how these treatments could be adapted for solid tumors, which make up roughly 30 percent of pediatric cancers and the majority of adult cancers.
Using CAR-T therapy against solid tumors is challenging because these malignancies have unique methods to evade the human immune system, making it difficult for the CAR-T cells to find and attack the cancer. Before CAR-T therapies become safe and effective in solid tumors several critical challenges need to be addressed, including:
- Efficient trafficking of CAR-T cells to the tumor
- Selecting the most appropriate tumor antigens to avoid on-target/off-tumor toxicity
- Overcoming the immunosuppressive tumor microenvironment
- Identifying and manufacturing the specific T-cell population with the greatest therapeutic potential.
The rapid pace of scientific progress within the CAR-T field is exciting for scientists, physicians, patients, caregivers, and has even been widely embraced by the general public. Many advancements have already been achieved or will make their way into clinics in the near future.
Avoiding toxic antigens
One of the initial steps in designing any CAR-T cell therapy is antigen selection, or choosing which tumor associated antigen to redirect the patient’s T cells to recognize. To avoid toxicity when CAR-T cells bind the target antigen expressed on normal tissues, researchers must identify antigens that are broadly expressed on tumor cells with limited to no expression in normal tissues.
Several developers are working to identify novel tumor-associated antigens and, many antigen targets are being studied in clinical trials in patients with solid tumors, including breast cancer, neuroblastomas, melanomas, prostate cancer, pancreatic cancers and others. To address off-tumor toxicity, some developers are looking at using multiple CAR-T receptors in the same cell and include dual CAR, tandem CAR, and inhibitory CAR designs. These alternative CAR-T receptor designs are similar to Boolean operators that use AND-gate circuits (the tumor must have both antigens expressed to activate the CAR-T cell), OR-gate circuits (the tumor could have either one or the other antigen to activate the CAR-T cell), and a NOT-gate circuit to inhibit the CAR-T in the presence of a specific antigen.
Other next-generation CAR-T designs can be used to address heterogeneous antigen expression and a major pathway of resistance to CAR-T cell therapy. Consistent with the insidious nature of cancer, tumor-specific antigens can be expressed heterogeneously, or inconsistently across the tumor cells within a patient. This results in a CAR-T therapy that does not completely eradicate tumor cells in a patient. In addition, tumors can develop resistance to targeted therapy through antigen loss, or effectively hiding from the CAR-T cells by discontinuing the expression of the target antigen in response to treatment. Antigen loss is a common mechanism of resistance in CAR-T treated hematological patients who experience a CD19-negative disease relapse after treatment with CD19-targeted CAR-T cells. Dual CAR-T cell therapies have recently entered the clinic in hematological malignancies and are being studied pre-clinically in solid tumors.
Overcoming Mechanisms of Resistance and Immunosuppression
Another approach featuring ‘switch’ and ‘universal’ CAR-T cell designs uses a targeting molecule (akin to a bispecific antibody) that binds to a receptor or protein on the engineered T-cells and a tumor antigen, effectively bringing the CAR-T cells into contact with tumor cells. Taking this approach a step further, multiple targeting molecules could be used in the same patient to redirect the engineered CAR-T cells to multiple antigens circumventing antigen loss.
A growing body of research has shown that tumors are connected to and communicate with their surrounding environment through a complex and diverse set of signaling pathways.In many patients, the tumor microenvironment (TME) favors immune suppression, and multiple research programs are focused on identifying ways to make the TME more pro-inflammatory and thus allowing the immune system to destroy the tumor. Multiple approaches are being developed focusing on the transgenic expression of specific cytokines (such as IL-15, IL-18, and others) to alter the TME.
Another approach to alleviate immunosuppressive forces within the TME is by inhibiting the PD-1 signaling axis with a checkpoint inhibitor. To date, monoclonal antibodies that inhibit the PD-1 pathway have been highly successful treating several solid tumors. Researchers are pursuing multiple paths to inhibit PD-1 signaling in the context of CAR-T cell therapy including driving expression of a truncated form of a PD-1 inhibitor by the CAR-T cells, knocking out the PD-1 receptor in CAR-T cells, and combining traditional CAR-T cells with approved checkpoint inhibitor antibodies.
The future is bright for CAR-T research
A common theme is evident – cancer is complex and as additional mechanisms of resistance and challenges are identified and better understood there are multiple solutions being developed by innovative teams for each challenge. Just as there are many disparate drivers of oncogenesis, there will be many distinct therapeutic designs and combinations of therapy that propel the field forward. Not all of these innovative therapies will succeed, but if the experiments and clinical trials are well designed using real world data to better inform them, they could become or lead to the next impactful breakthrough we are all hoping for.
As more and more challenges to treating solid tumors with adoptive cell therapy are identified and understood, a growing number of scientific innovations and variations on CAR-T cell therapy are being designed and tested. At We are working with patients and investigators that are motivated to join these exciting trials, using real-world data and analytics to drive them forward.
It often feels like science is moving faster than the steady cadence of clinical trials. As patients become better educated about the promise of CAR-T cell therapies, many clinical research sites are accumulating growing waiting lists of patients who want to enroll in these trials. But patients alone are not enough.
In comes the need for human data science; when sponsors find the right combination of human science and data science, they will be able to streamline trials and accelerate the development process.
A successful CAR-T clinical trial not only requires an understanding of the right sites; the sponsor must also partner with experienced teams who know how to work through the nuances of regulatory submission, training of site staff, and resourcing the trial for monitoring – while working through huge amounts of data. They must also have a robust and streamlined safety reporting process, and understand the details around all of the critical logistical steps required to manufacture and treat patients with highly personalized and potentially toxic cellular therapies.
The road ahead for CAR-T cell therapy has many obstacles – both known and unknown; however, the value of these adoptive cell therapies to patients is clear.