Health & Wellness

There is great potential for CAR-T cell therapy to transform the treatment of solid tumors, but it comes with its own challenges.

 From issues with tumor markers to the challenges of the tumor environment, adapting this immunotherapy for solid tumors requires innovative approaches and persistent research. With Dr. Davendra Sohal as our guide, Director of Experimental Therapeutics at the University of Cincinnati Cancer Center, let's explore the promising developments in CAR T-cell therapy for solid tumors, the hurdles we are working to overcome, and the future directions that could reshape the treatment landscape for patients faced with cancer. .

What is CAR T-Cell Therapy?

CAR T-cell therapy is a groundbreaking approach to  cancer treatment, using the power of a cancer patient’s own immune system to combat cancer more effectively. This innovative therapy involves several key steps:

• Cell Collection: The process begins with the collection of T-cells, a type of immune cell, from the cancer patient’s blood. This is done through a procedure similar to a blood donation.
• Cell Modification: Once collected, these T-cells are transported to a specialized laboratory where they are genetically engineered to produce Chimeric Antigen Receptors (CARs) on their surface. These CARs are designed to recognize specific proteins present on cancer cells.
• Cell Expansion: The modified T-cells are then multiplied in the lab to create a large number of CAR T-cells, ensuring enough to target the cancer in the patient effectively.
• Infusion: The expanded CAR T-cells are infused back into the cancer patient’s bloodstream, where they seek out the cancer cells that express the targeted antigen.

This therapy has already demonstrated impressive success in treating certain blood cancers, such as leukemia and lymphoma. Now, researchers, including those at the University of Cincinnati Cancer Center, are working to adapt this technology to address the more complex challenge of solid tumors. By enhancing the ability of CAR T-cells to identify and attack cancer cells within solid tumors, this therapy holds the promise of offering new treatment options for cancer patients.

Challenges in Treating Solid Tumors

While CAR T-cell therapy has shown remarkable success in treating blood cancers, applying it to solid tumors presents a range of unique challenges. These obstacles include:

• Antigen Loss: Unlike blood cancers, solid tumors can sometimes stop expressing the targeted tumor-associated antigens (TAAs), making it difficult for CAR T-cells to recognize and attack the cancer cells. When the target is no longer present, the therapy’s effectiveness is significantly reduced.
• T Cell Exhaustion: Over time, CAR T-cells can experience exhaustion, where they become less effective at attacking cancer cells. This phenomenon can limit the durability of the treatment response and reduce the overall effectiveness of the therapy.
• T Cell Trafficking and Tumor Infiltration: Getting CAR T-cells to penetrate and effectively infiltrate solid tumors is a major challenge. The dense structure of solid tumors can act as a barrier, preventing CAR T-cells, and even naturally occurring tumor-infiltrating lymphocytes (TILs), from reaching the cancer cells effectively.
• Immunosuppressive Tumor Microenvironment (TME): The environment surrounding solid tumors can be highly suppressive, creating conditions that inhibit immune responses. This immunosuppressive TME can diminish the activity of CAR T-cells, TILs, and other immune cells, hindering their ability to destroy cancer cells.

Addressing these challenges requires ongoing research and innovative approaches to optimize CAR T-cell therapy for solid tumors. Understanding and overcoming these obstacles are crucial steps in translating the success of CAR T-cell therapy from blood cancers to solid tumors.

Strategies to Overcome Challenges

To address the unique challenges associated with CAR T-cell therapy for solid tumors, ongoing cancer research is exploring several innovative strategies:

• Local Administration: One approach is to directly inject CAR T-cells into the tumor site. This local administration can potentially increase the concentration of CAR T-cells in the tumor, enhancing their ability to target and destroy cancer cells while minimizing systemic side effects.
• Chemokine Receptors: Engineering CAR T-cells to express chemokine receptors is another strategy being explored. These receptors guide the CAR T-cells to the tumor site by attracting them to the tumor's environment, improving their ability to infiltrate and attack solid tumors.
• Tumor Stroma Penetration: Researchers are developing CAR T-cells that can better penetrate the tumor stroma, the supportive tissue surrounding tumors. By enhancing the ability of CAR T-cells to navigate this dense and often fibrous tissue, they can reach and target cancer cells more effectively.
• Combination Therapies: Combining CAR T-cell therapy with other treatments is also being investigated. Potential combinations include chemotherapy, which can help to reduce the tumor burden; radiotherapy, which can enhance CAR T-cell activity; oncolytic viruses, which can selectively kill tumor cells and stimulate immune responses; and immune checkpoint inhibitors, which can help overcome the immunosuppressive TME.

Promising Targets for Solid Tumors

Identifying effective targets is crucial for the success of CAR T-cell therapy in treating solid tumors. Researchers are focusing on various potential targets to enhance the precision and effectiveness of this therapy:

• Protein Antigens (TAAs): Several protein TAAs have emerged as promising targets for CAR T-cell therapy. These include:
  • HER2: Overexpressed in certain cancers like breast and gastric cancer.
  • EGFR: Found in a range of solid tumors, including colorectal cancer and non-small cell lung cancer.
  • CEA: A marker present in several cancers, such as colorectal cancer.
  • ROR1: Expressed in various solid tumors and some normal tissues.
  • NKG2D Ligands: Found on many cancer cells, including those in solid tumors.
  • B7-H3: Present in several cancers, including breast and prostate cancer.
  • CD70: Expressed in certain solid tumors, such as renal cell carcinoma.
  • CLDN18.2: Found in gastric and pancreatic cancers.
  • Mesothelin: Overexpressed in cancers like mesothelioma and ovarian cancer.
• Carbohydrate Antigens: In addition to protein antigens, researchers are exploring carbohydrate antigens as targets for CAR T-cell therapy. These include:
  • Heparan Sulfate Proteoglycans (HSPGs): Found in various tumors and associated with cancer progression.
  • Mucin Glycans: Present in several types of cancer, including pancreatic and ovarian cancers.
  • Gangliosides: A group of sialic acid-containing glycosphingolipids found on the surface of many tumor cells.
  • Blood-Group Related Lewis Antigens: Associated with several cancers, including colorectal cancer.

Types of Solid Tumors Being Studied

Researchers are actively investigating the application of CAR T-cell therapy across a range of solid tumors, aiming to expand the benefits of this innovative treatment beyond blood cancers. Some of the key types of solid tumors being studied include:

• Brain Tumors: Glioblastoma, one of the most aggressive brain tumors, is a primary focus. Efforts are underway to develop CAR T-cells that can cross the blood-brain barrier and effectively target brain tumor cells.
• Lung Cancer: Research is exploring the use of CAR T-cell therapy for non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Identifying effective targets and overcoming the challenges of tumor heterogeneity and the immune-suppressive environment are crucial for success in this area.
• Breast Cancer: CAR T-cell therapy is being adapted for various subtypes of breast cancer, including HER2-positive breast cancer. Studies aim to improve the precision of CAR T-cells to target specific antigens expressed in these tumors.
• Colorectal Cancer: Research is focused on targeting antigens such as CEA and other markers specific to colorectal cancer. The goal is to develop CAR T-cells that can effectively address this common and challenging cancer type.

These types of solid tumors represent a significant portion of cancer cases and are the focus of ongoing research to determine how CAR T-cell therapy can be tailored to address their unique characteristics and treatment challenges.

Current Status of Research

CAR T-cell therapy for solid tumors is a rapidly evolving field, with ongoing research and clinical trials aiming to determine the safety, efficacy, and broader applicability of this innovative treatment. Here’s an overview of the current status:

• Experimental Stage: CAR T-cell therapy for solid tumors is still largely in the experimental phase. While progress has been significant, these therapies are not yet widely available outside of clinical trials. Researchers are working to refine the approaches and demonstrate their effectiveness through rigorous testing.
• Clinical Trials: Numerous clinical trials are underway to evaluate CAR T-cell therapies for various solid tumors. These trials are essential for understanding how well these therapies work in humans, their potential side effects, and how they compare to existing treatments.
• Patient Considerations: For patients interested in CAR T-cell therapy, participating in clinical trials may be the best option to access these cutting-edge treatments. It is important for patients and caregivers to discuss current options and potential clinical trial opportunities with their care team to make informed decisions about their treatment plans.
• Advancements and Innovations: Researchers are continuously making strides in enhancing CAR T-cell therapy, including developing new targets, improving CAR T-cell persistence, and exploring combination therapies. These advancements aim to overcome the challenges associated with treating solid tumors and bring effective options to patients.

Here at the University of Cincinnati Cancer Center, we were chosen as one of the first sites in the world for a new trial testing whether CAR-T therapy could work against solid tumors, which could give hope to patients who have exhausted all other options.

“We have excellent expertise in doing clinical trials and cell therapies and building on our blood cancer experience to take it to the next level, which is solid tumors,” says Dr. Sohal.

Overall, while CAR T-cell therapy for solid tumors holds great promise, it is essential for ongoing research to validate its effectiveness and establish protocols for its safe and effective use in a broader patient population.

Future Directions

The future of CAR T-cell therapy for solid tumors is filled with potential as researchers and clinicians continue to push the boundaries of this treatment. Several key areas of focus are shaping the future of CAR T-cell therapy:

• Multi-Specific CAR T-Cells: One exciting development is the creation of multi-specific CAR T-cells that target multiple antigens simultaneously. This approach aims to enhance the ability of CAR T-cells to recognize and attack tumors that may have heterogeneous or varying antigen profiles, potentially improving treatment outcomes.
• Enhanced Persistence and Functionality: Researchers are working on strategies to improve the longevity and effectiveness of CAR T-cells within the hostile tumor microenvironment. Enhancing CAR T-cell persistence and functionality through methods like optimized T cell expansion could lead to more durable responses and prolonged efficacy in combating solid tumors.
• Combination Therapies: The exploration of combination therapies is a significant area of research. Combining CAR T-cell therapy with other treatments, such as immune checkpoint inhibitors, oncolytic viruses, or targeted therapies, may enhance overall efficacy and overcome some of the challenges associated with treating solid tumors.
• Personalized Approaches: The future may also see more personalized CAR T-cell therapies tailored to individual patients’ tumor profiles. By customizing CAR T-cell treatments based on specific genetic and molecular characteristics of each patient’s tumor, researchers aim to optimize the therapy's effectiveness and minimize side effects.
• Broader Applications: As research progresses, CAR T-cell therapy may expand to address a wider range of solid tumors beyond those currently under investigation. The continued development and validation of new targets and strategies will be crucial for broadening the applicability of this promising therapy.

Overall, the future of CAR T-cell therapy for solid tumors is promising, with ongoing research and innovation expected to overcome existing challenges and provide new treatment options for patients facing these difficult cancers.