Targeting Cancer Stem Cells and Immunotherapy in Colorectal Cancer Treatment

Jump To Section

• Cancer Stem Cells Explained
• Treatment Resistance Challenge
• Immunotherapy Potential in Colon Cancer
• MSI Biomarker and Patient Selection
• Future Research Directions
• Full Transcript

Cancer Stem Cells Explained

Dr. Hans-Joachim Schmoll, MD, identifies cancer stem cells as the fundamental origin of colorectal cancer. These tumor-initiating cells possess unique strength to overcome the body's immune defenses and local resistance mechanisms. Dr. Hans-Joachim Schmoll, MD, explains that while the body constantly develops and kills off most abnormal cells, a rare few escape. These escaping cells are the cancer stem cells, which have a significant growth advantage over normal tissue cells.

These powerful cells can divide and create a heterogeneous tumor. They generate both less malignant clones and, critically, new cancer stem cells that can be even more aggressive. A clinically detectable colon cancer tumor is therefore not a single entity but a collection of different cancer stem cell lineages. This understanding is pivotal for developing effective treatments.

Treatment Resistance Challenge

A major hurdle in colorectal cancer treatment is the innate resistance of cancer stem cells. Dr. Hans-Joachim Schmoll, MD, states that these cells are typically more resistant to chemotherapy and immunotherapy compared to their daughter cells. He provides a common clinical scenario: a patient with metastatic colon cancer responds well to chemotherapy, eliminating perhaps 90% of the tumor burden.

However, the remaining 10% of residual disease often contains these resilient cancer stem cells. While surgery can resect macroscopic disease, it cannot address microscopic residual stem cells. These surviving cells are the source of local recurrence and the development of new, distant metastases. This underscores the central challenge in oncology: finding a way to definitively kill the cancer stem cell itself.

Immunotherapy Potential in Colon Cancer

Immunotherapy represents a promising new avenue for attacking cancer stem cells. Dr. Hans-Joachim Schmoll, MD, describes it as a method to reactivate the body's own immune cells, specifically T-cells, to attack the tumor. Checkpoint inhibitor medications can unleash these T-cells, allowing them to kill cancer cells. This approach has shown remarkable success as a last-line and now first-line therapy in other cancers like melanoma and kidney cancer.

Dr. Hans-Joachim Schmoll, MD, notes that, unfortunately, immunotherapy has not shown broad efficacy in colorectal cancer at present. The key is activating the immune system to recognize and destroy the tumor cells, including the elusive stem cells. The interviewer, Dr. Anton Titov, MD, explores this potential, highlighting the need to understand why response rates differ so significantly across cancer types.

MSI Biomarker and Patient Selection

Patient selection is paramount for immunotherapy success in colon cancer. Dr. Hans-Joachim Schmoll, MD, identifies a specific subgroup comprising 5% to 15% of patients who may benefit. These patients have tumors with a characteristic known as MicroSatellite Instability-high (MSI-H). MSI-H colon cancers have a very high mutation rate, which makes them more visible and attractive to the immune system.

This high mutational load draws many immune T-cells into the tumor microenvironment. When treated with immune checkpoint inhibitors, these pre-existing T-cells become activated and can effectively attack the cancer. For this specific MSI-positive patient population, immunotherapy is a very active and potent treatment option. This breakthrough underscores the importance of biomarker testing in personalizing cancer care.

Future Research Directions

The future of colorectal cancer treatment hinges on continued research. Dr. Hans-Joachim Schmoll, MD, emphasizes that for the vast majority of colon cancer patients (85-95%), current immunotherapy offers no efficacy. The primary goal is to expand the benefits of immunotherapy to a larger patient cohort. This requires a deeper understanding of cancer stem cell biology and the tumor immune microenvironment.

Research is focused on finding the right molecular keys to target and kill the variable and evolving cancer stem cells. Dr. Schmoll is confident that future studies will reveal how to harness immunotherapy more effectively against colon cancer stem cells. The ultimate aim is to use the patient's own activated immune system as the optimal means to eliminate all tumor cells and achieve a cure.

Full Transcript

Dr. Anton Titov, MD: Cancer stem cells hold keys for cure of colorectal cancer. How can cancer stem cells be found and killed by new cancer treatments? How to use immunotherapy to cure colorectal cancer in carefully chosen patients?

Dr. Hans-Joachim Schmoll, MD: Colon cancer stem cells or tumor-initiating cells are the reason for systemic chemotherapy failure in colon cancer treatment.

Dr. Anton Titov, MD: You have a very large experience in advancing stem cell technologies for treatment of colorectal cancer. What is the role of cancer stem cells in colorectal cancer? What advances in stem cell technologies can help colorectal cancer treatments?

Dr. Hans-Joachim Schmoll, MD: The key to any cancer is the cancer stem cell. Cancer stem cell is exactly the cell that was strong enough to overcome the immune system. Cancer stem cells can overpower local resistance mechanisms to the developing tumor cells so that tumor can develop.

At any time in our body we develop cancer cells. But the vast majority of the cancer cells are killed. Cancer cells die on their own, or immune cells kill most developing cancer cells. But there are few cancer cells that escape body defense at some time point.

This cancer cell escape is possible because cancer stem cells are strong enough and deviant enough from the normal tissue cells. Cancer cells have a growth advantage over normal cells. Cancer cells must be killed at the right time.

Cancer stem cells can really grow fast. Cancer stem cells divide. They can easily develop into less malignant clones, but also cancer stem cells can develop more malignant clones in time. Then they can also develop other cancer stem cells. Some of new cancer stem cells are even more malignant than the primary stem cell.

We detect colon cancer tumor by colonoscopy, for example, or by CT or MRI or PET during metastatic cancer investigation. Clinically detected cancer has a collection of different cancer stem cells that are derived from the initial cancer stem cell.

The problem is this. Cancer stem cells are usually more resistant to any chemotherapy. Cancer stem cell is also resistant to immunotherapy in comparison to its daughter cells.

For example, you can give chemotherapy to a tumor like colon cancer with metastases in the liver. The patient is lucky and the treatment works very well. Then we can probably eliminate 90% of the tumor cells in the liver and in the body by the chemotherapy. But that 10% of residual cancer contains cancer stem cells.

We can resect remaining 10% of tumor by surgery. But this is a macroscopic treatment of tumor. Surgery is not a microscopic management. This is a problem.

Microscopic stem cells reside in remaining tumor. They can develop new metastases at the same place, or they also migrate to other organs and do further metastasis. This is the key to cancer treatment.

How to kill the cancer stem cell? Even if it is possible to kill most of the "daughter cells" of colon cancer tumor. It is not clear now how to kill cancer stem cells. What is the best molecular key to find and kill cancer stem cells?

There are many antibodies developed. But the problem is cancer stem cells are variable. Cancer stem cells evolve. It is not so easy to find one molecule that will kill all cancer stem cells.

Someday we will kill cancer stem cells. But for now a lot of research is necessary to fight cancer stem cells.

There is another option to kill cancer stem cells. It is probably more helpful and very recent method. It is immunotherapy. Immunotherapy is surprisingly active in other tumors, in kidney cancer or melanoma.

This is real immunotherapy. It means we let immune cells attack the tumor cells. Even when body's own immune system was not working normally. Otherwise a tumor would not grow.

T-cell checkpoint inhibitors can activate immune T-cells. Such toxic T-cells can kill the tumor. Immunotherapy works in many tumor types. It is very good last-line treatment. Now it is going to first-line therapy.

But in colorectal cancer immunotherapy doesn't work very well at the moment. We think the key is to select a specific subgroup of colon cancer patients. It is 5 to 10% of patients.

It is important to let the immune cells do their work in the tumor cells and colon cancer stem cells. I'm sure in few years the research will show how to use immunotherapy to kill colon cancer stem cells. But this is the optimal means to eliminate the tumor cells just by the activated normal human immune cells.

It is also a question of selecting the right patients for immunotherapy.

Dr. Anton Titov, MD: Those 5% to 10% of colon cancer patients. Immunotherapy might work for them even at the present level of technology.

Dr. Hans-Joachim Schmoll, MD: There is specific group of colon cancer patients for whom immunotherapy may work. These tumors have MSI characteristic. MSI is MicroSatellite Instability.

MSI colon cancers have a particularly high mutation rate in the tumor. High mutation rate inside tumor attracts many immune T-cells into the tumor. T-cells are activated by immune checkpoint inhibitor medications.

Checkpoint inhibitors are antibodies for colorectal cancer treatment. Immune checkpoint inhibitors are very active in MSI-positive colorectal cancer. But these are only 5% to 15% of all colon cancers. It depends on the patient population.

For the majority of colon cancer patients immune checkpoint inhibitors have no efficacy. We need to do more research on immunotherapy for colon cancer. We hope that immunotherapy research will bring results for patients in the near future. Thank you.