CAR T-cell: Advances in Adoptive Therapies for Targeting Heterogeneity in mCRPC Lupita Lopez

By Lupita Lopez, BS

Ph.D. candidate at the City of Hope Campus

There are two distinct subtypes of metastatic castration-resistant prostate cancer (MCRPC): prostate adenocarcinoma and neuroendocrine prostate cancer. At City of Hope, under the leadership of Dr. Priceman, we are studying the targeting of PSCA with a PSCA CAR, which would target prostate adenocarcinoma. My focus is on combining this approach with targeting CEA in neuroendocrine prostate cancer. The literature suggests that up to 20% of MCRPC can be NEPC in nature, but we have observed antigen heterogeneity within patient samples here at City of Hope, indicating that it varies from patient to patient.

What are the current treatment options for mCRPC, and how effective are they in addressing the heterogeneity of the disease?

Current treatment options for MCRPC are not curative. However, they include chemotherapy, second-generation androgen deprivation therapies, radioligand therapies, and an FDA-approved cancer vaccine. These treatments aim to prolong patient progression-free survival, overall survival, and quality of life. Therefore, the focus should be on finding a curative therapy for MCRPC.

How do adoptive T-cell therapies work, and how have they been developed to target the heterogeneity of mCRPC?

Adoptive T-cell therapy is a type of immunotherapy where a patient’s immune cells are extracted, expanded ex vivo, and then reinfused back into the patient. There are different forms of ACT, including tumor-infiltrating lymphocytes, TCR-based ACT, and CAR T-cell therapy.

Dr. Priceman and his lab focus on developing CAR T-cells for solid tumors, specifically for MCRPC. CAR T-cells are chimeric antigen receptors that have an antigen recognition domain, a linker transmembrane domain, and intracellular signaling domains that help the T-cell recognize the tumor’s antigen. My focus is on developing a PSEA CAR with a CEA antigen recognition domain, which we call a tandem CAR. We combine this with the PSEA clinical CAR construct we have on campus.

What is the potential of adoptive T-cell therapies in treating mCRPC, and what are the challenges associated with their development and implementation?

There is a lot of potential with adoptive cell therapies. Currently, the PSCA CAR construct is in the CAR trial here on campus, and PSMA CAR T-cells are also being actively investigated. The ultimate goal of these therapies is not only to target MCRPC but also to trigger an endogenous immune system response with all the inflammatory signals that occur during the activation of the CAR constructs.

However, finding the right combination of CAR with the patient is challenging. Moreover, there are concerns regarding the long-term efficacy of the T-cell product, which should expand and have lasting effects in the patient. Another challenge is antigen escape issues. We are actively investigating these issues with the tandem CAR.

If we target PSCA, we do not want the antigen-negative or PSCA-negative tumor to escape. Hence, we are introducing the CEA SCFV into the CAR construct. Additionally, the hostile tumor microenvironment poses further challenges as there are immune inhibitory cells and proteins that limit the efficacy of CAR T-cells.

What are the latest advancements in adoptive T-cell therapies for mCRPC, and how do they compare to other emerging treatments for the disease?

As I mentioned, there are the PSCA CAR and PSMA CAR therapies, both of which have shown transient responses. Their persistence and safety are still being evaluated in phase one clinical trials. Additionally, there is radioligand therapy using PSMA, an antigen expressed in prostate adenocarcinoma. The FDA recently approved a PSMA lutetium, which is a PSMA antibody with a radio ligand. Researchers are investigating its use in combination therapies. However, these therapies are not curative and only work to extend survival and improve quality of life. More research needs to be done.

How can the efficacy and safety of adoptive T-cell therapies be optimized for patients?

The most crucial aspect is ensuring that the patient’s tumor expresses the targeted antigen, such as PSCA or CEA. Additionally, there are specific criteria that patients must meet to participate in clinical trials. The patient’s prior therapy history can also affect the effectiveness of the T-cell therapy being developed. For instance, if a patient has undergone several rounds of chemotherapy or radiation, their T-cell product may not be as effective, and additional apheresis may be necessary. Further research is needed to optimize the safety and efficacy of adoptive T-cell therapies for patients.

How can they collaborate with other healthcare professionals and oncologists to ensure the best outcomes for their patients?

We have a mouse model here at the City of Hope. Dr. Priceman and staff scientist Dr. John Murad have worked on developing a syngeneic mouse model with human PSCA expressed in these mice, where the mouse PSEA would typically be expressed. This allows us to evaluate the safety and efficacy of CAR T-cells.

This is one way we can optimize safety and efficacy, in addition to combining therapies such as radiation or other immune proteins to activate T-cells.

Patient education and support can be improved to help those with mCRPC make informed decisions about treatment options, including adoptive T-cell therapy. Oncologists have a crucial role in interacting with patients to determine if these therapies are effective. Collaboration with our PI, Dr. Priceman, and our team is essential for overseeing these trials.

How can they collaborate with other healthcare professionals and oncologists to ensure the best outcomes for their patients?

At City of Hope, there is a Department of Supportive Care Medicine that offers patients and their loved ones access to educational resources about their treatment options. In addition, patients can receive support from psychiatrists, psychologists, clinical social workers, and childcare specialists.

The institution takes a holistic approach to help patients during this difficult time. If every institution could adopt this approach, it would be amazing, and we are on the right track.

Final Thoughts On the AACR 2023 Abstract 4104

I think it’s an exciting time for personalized medicine and immunotherapy. There’s a lot of exciting work being done here at City of Hope and at other institutions to make the best and safest immunotherapies. I would especially like to thank my mentor, Dr. Priceman, and Dr. Tanya Dorff, who is in charge of the PSEA CAR clinical trial here on campus.

What Are Adoptive T-cell Therapies?

Adoptive T-cell therapy is a type of cancer treatment that involves using the patient’s own immune cells to attack cancer cells. It is a form of immunotherapy, which seeks to harness the body’s immune system to fight cancer.

The therapy involves removing T-cells (a type of white blood cell) from the patient’s body, genetically modifying them in the lab to target specific cancer cells, and then infusing the modified cells back into the patient’s body. The modified T-cells then seek out and destroy cancer cells.

There are two main types of adoptive T-cell therapy: T-cell receptor (TCR) therapy and chimeric antigen receptor (CAR) therapy. TCR therapy involves modifying T-cells to recognize specific antigens on the surface of cancer cells. CAR therapy involves modifying T-cells to express a receptor (CAR) that recognizes a specific protein on the surface of cancer cells.

Adoptive T-cell therapy has shown promise in treating certain types of cancer, including leukemia and lymphoma. In some cases, it has led to complete remission of the disease. However, the therapy is still in its early stages of development, and more research is needed to determine its long-term effectiveness and safety.

Adoptive T-cell therapy is a personalized treatment, as each patient’s T-cells are modified specifically for their own cancer cells. It is also a complex and expensive treatment, requiring specialized facilities and expertise. As a result, it is currently only available at a limited number of medical centers.

Despite its challenges, adoptive T-cell therapy holds great potential as a new approach to cancer treatment. As research continues, it may become an important part of the arsenal against cancer, offering hope to patients who previously had few treatment options.

10 Key Takeaways from the AACR 2023 Abstract 4104

1. Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with a complex molecular and cellular landscape, making it difficult to treat with conventional therapies.

2. Adoptive T-cell therapies, which involve the engineering and infusion of patient-derived T-cells that are designed to recognize and kill cancer cells, have shown promising results in preclinical and early clinical studies.

3. One approach to developing effective adoptive T-cell therapies for mCRPC involves targeting tumor-specific antigens (TSAs) that are expressed exclusively or preferentially by cancer cells.

4. Another approach involves targeting shared or overexpressed antigens, such as prostate-specific membrane antigen (PSMA), which is expressed on the surface of most prostate cancer cells and can be recognized by T-cells engineered to express chimeric antigen receptors (CARs).

5. Strategies to overcome the immunosuppressive tumor microenvironment (TME) in mCRPC are critical for the success of adoptive T-cell therapies. These may include using immune checkpoint inhibitors, cytokines, or other immunomodulatory agents.

6. The development of personalized vaccines that target patient-specific neoantigens (NSAs) may also be a promising strategy for treating mCRPC.

7. Combination therapies that integrate adoptive T-cell therapies with other modalities, such as chemotherapy, radiotherapy, or targeted therapies, may enhance their efficacy by increasing the availability of targets or enhancing immune activation.

8. The success of adoptive T-cell therapies for mCRPC will require the development of biomarkers to predict response and monitor treatment efficacy, as well as the optimization of manufacturing processes to ensure reproducibility and safety.

9. Patient selection is critical for the success of adoptive T-cell therapies, as patients with heavily pretreated disease, significant comorbidities, or limited immune function may be less likely to benefit from these treatments.

10. Finally, the high cost and complexity of adoptive T-cell therapies may limit their widespread adoption, highlighting the need for ongoing research to optimize their efficacy and cost-effectiveness.

Lupita Lopez, BS – About The Author, Credentials, and Affiliations

Lupita Lopez earned her Bachelor of Science degree in Molecular Cell Biology from California State University, Long Beach. She grew up in Fountain Valley, California, and is currently pursuing her Ph.D. at the Irell & Manella Graduate School of Biological Sciences at City of Hope. In 2018, Lupita was awarded the H.N. & Frances Berger Foundation Fellowship. Her doctoral research is focused on creating new CAR T cells for cellular immunotherapy to treat metastatic prostate cancer.