Chimeric Antigen Receptor T-Cell Therapy: A Longitudinal Study Conner Johnson MD

By Conner Johnson, MD

Chimeric antigen receptor (CAR) T-cell therapy is an immunotherapy treatment that has transformed the landscape for those with relapsed refractory hematologic malignancies. It is a treatment where we take white blood cells from a patient and create an autologous product that is an altered version of T-cells, which express an antigen receptor targeting the cancer. Then, those cells are rein-fused back into the patient. This treatment is approved in the relapse refractory setting for certain subtypes of non-Hodgkin’s lymphoma, multiple myeloma, and acute lymphoblastic leukemia. It has remarkable outcomes in the relapse refractory setting, affording patients treatment options that were previously not available.

What are the unique logistics and toxicities associated with CAR-T cell therapy in this clinical trial?

CAR T-cell therapy is a unique treatment, partially because it involves multiple steps. The first step, called aphaeresis, requires the collection of T-cells from the patient. The second step involves CAR T-cell manufacturing, which can take approximately 3 to 4 weeks to generate the CAR T-cell product. Generally, viruses are used to manufacture the CAR T-cell product, which is then sent back to the treating center. Before the patient receives CAR T-cell therapy, they may need bridging therapy to control the malignancy while awaiting the product’s manufacture. Then, a few days before the CAR T-cells are infused, lympho-depleting chemotherapy is administered to prevent rejection of the CAR T-cells. The CAR T-cells are infused as a single infusion, usually in the inpatient or outpatient setting, with the inpatient setting being the typical choice for most patients.

CAR T-cell therapy has unique side effects. It can cause cytopenias, hypogammaglobulinemia, and B-cell aplasia, particularly when given to lymphoid malignancies, for the latter toxicity. However, the most significant toxicities are cytokine release syndrome and neurologic toxicity, also known as immune cell-associated neurologic toxicity syndrome or ICANS. Both of these toxicities are mediated by cytokine secretion from CAR T-cell expansion and proliferation. There are treatments for these toxicities, but they are unique and are not the typical toxicities seen with standard chemotherapy.

What are patient-reported outcomes (PROs) and why are they important in assessing the effectiveness of CAR-T cell therapy?

CAR T-cell therapy has multiple different approvals. For example, there are six FDA-approved products for aggressive large B-cell lymphomas. CAR T-cell therapy can yield durable remissions at a rate of up to 40% in patients who previously had median survivals of only 6 months. Additionally, there are other indications for CAR T-cell therapy. However, patient-reported outcomes (PROs) are becoming a more critical component of clinical trial design, as they are clearly essential to patients and family members. There is a relative paucity of information available about patient-reported outcomes (PROs), such as quality of life, in CAR T-cell therapy. There have been some studies that have looked at small numbers of patients or have focused on single CAR T-cell therapy products. However, patients also want to know the impact of therapies, not just on length of life, but on patient-reported outcomes (PROs) such as quality of life.

“In this space, we sought to conduct a longitudinal perspective study looking at patient reported outcomes, and we focused on quality of life as well as psychological symptoms including anxiety symptoms, depression symptoms, and post-traumatic stress disorder symptoms, as well as physical symptoms.” Conner Johnson, MD, Massachusetts General Hospital

What were the time points at which PROs were assessed, and how did they change over time?

We measured patient-reported outcomes (PROs) at baseline, meaning prior to CAR T-cell therapy infusion, and at 1 week, 1 month, 3 months, and 6 months after CAR T-cell therapy infusion. The primary patient-reported outcome for this study was quality of life, though we also examined psychological and physical symptom burden. Notably, quality of life dropped at the 1-week time point compared to baseline, then improved near baseline by the 1-month time point. By the 3-month time point, quality of life had actually improved on average and this improvement persisted at the 6-month post-CAR T-cell therapy mark. A similar pattern was observed for depression symptoms, physical symptom burden, anxiety symptoms, and PTSD symptoms. Generally, all patient-reported outcomes (PROs) had a positive trajectory on average for patients from baseline to the 6-month timeline.

What factors were associated with the QOL trajectory after CAR-T infusion?

The overall sample size for this study was 100 patients, which still left us with relatively limited ability to extensively search for predictors of quality of life trajectory. Interestingly, some factors associated with a more positive quality of life trajectory included the use of Tocilizumab, which is the IL6 receptor antibody for cytokine release syndrome, and the use of corticosteroids for toxicities. Perhaps the use of these therapies is just associated with a relatively greater improvement compared to baseline, as they can be associated with a greater tumor burden or there are some studies showing a linkage between IL6 and certain psychological symptoms. It is unclear what the mechanism is, and we did not have the sample size to assess that, but it is interesting to note that the use of Tocilizumab and corticosteroids was associated with a relatively greater improvement in quality of life over time.

What interventions are needed to support patients with psychological distress and physical symptoms longitudinally after CAR-T infusion?

I do want to note that although the trajectory for quality of life, and the other patient-reported outcomes (PROs) we’ve discussed, showed improvement over time, about 20% of patients had persistent clinically significant anxiety, depression, and/or PTSD symptoms at the 6-month time point, and a subset of patients also had moderate or severe physical symptom burden at the same time. However, those percentages were numerically better than those seen at baseline.

What this means is that at least for a significant minority of patients, there is persistent physical and psychological symptom burden, and I do think that this leaves room for improvement in ways to optimize the patient-reported outcome experience longitudinally for these patients. One element to this could be supportive care interventions, such as palliative care interventions or other types of care delivery interventions designed to try and mitigate the physical and psychological symptoms experienced by patients. However, another set of interventions can be continued improvement in how we address and mitigate toxicities experienced by CAR T-cell therapy, whether that be newer CAR T-cell products, combination strategies, or prophylaxis strategies.

What are the implications of this study for future research and clinical practice in CAR-T cell therapy?

I think there are several, or I hope there are several. Firstly, I would note that this study adds to the existing literature, providing patients and clinicians with some expectations for longitudinal quality of life trajectory. It’s important to note that the majority of patients in this study had lymphoma, but a subset had myeloma, and one had ALL. The overall trajectory did not appear to be correlated with histology, and quality of life improved by the 3-month time point. This information can help clinicians counsel patients about the average quality of life trajectory when undergoing CAR T-cell therapy.

Secondly, I would like to point out that future studies should build upon this one. It was a single-center study with limited racial and geographic diversity, and larger studies with more diverse patient populations can expand our knowledge of the longitudinal patient reported outcome trajectory and identify additional predictors of those at the highest risk of poor patient reported outcomes.

Finally, I hope this study leads to additional research seeking to improve patient reported outcomes. This could involve supportive care interventions designed to mitigate physical and psychological symptom burden, or newer CAR T-cell products, combination strategies, and prophylactic strategies to reduce toxicities.

“I think the last point I would make is though of course there’s still room for growth and improvement in overall under our understanding and knowledge base around patient reported outcomes and how to optimize them. It is reassuring to see that patient reported outcomes on average improved by the 3 month time point over a sample size of around a hundred patients receiving CAR T-cell. We did not have the sample size to assess the etiology or mechanism of the improvement for patient reported outcomes, but we do suspect that this is primarily driven through improvement in disease related symptoms, just given the overall high response rates. We had a small number of patients who did not respond to CAR T-cell therapy, and they did not have the same longitudinal trajectory that those patients who had a response did, which is what is the major driver of our hypothesis, and hopefully future studies with larger patient sample sizes can really further elucidate the mechanism of how CAR T-cell therapy improves patient reported outcomes.” Conner Johnson, MD, Massachusetts General Hospital

What is Chimeric Antigen Receptor T-Cell Therapy?

Chimeric antigen receptor (CAR) T-cell therapy is a type of immunotherapy that uses genetically modified T cells to treat cancer. T cells are a type of white blood cell that play a critical role in the immune system’s response to infections and diseases.

In CAR T-cell therapy, T cells are collected from a patient’s blood, genetically engineered in a lab to produce chimeric antigen receptors (CARs) on their surface, and then infused back into the patient’s bloodstream. These CARs enable the T cells to recognize and bind to specific proteins on the surface of cancer cells, which then triggers the T cells to attack and destroy the cancer cells.

CAR T-cell therapy has shown promising results in treating certain types of cancer, including leukemia and lymphoma. However, it is still a relatively new and complex form of cancer treatment, and researchers continue to explore its potential uses and limitations.

10 Key Takeaway from the Chimeric Antigen Receptor T-Cell Therapy Clinical Trial

1. The study is focused on analyzing longitudinal patient-reported outcomes (PROs) in patients receiving Chimeric Antigen Receptor T-cell therapy (CAR-T).

2. CAR-T therapy is a type of immunotherapy that uses genetically modified T cells to target cancer cells. It has shown promising results in the treatment of certain blood cancers.

3. The study included 55 patients with relapsed or refractory blood cancers who received CAR-T therapy at a single center in the United States.

4. The researchers collected PRO data at multiple time points throughout the treatment process, including before treatment, during treatment, and after treatment.

5. The PRO measures included physical symptoms, psychological distress, quality of life, and overall satisfaction with treatment.

6. The study found that patients reported significant improvements in physical symptoms, psychological distress, and quality of life after CAR-T therapy.

7. Patients also reported high levels of satisfaction with the treatment, with most patients indicating that they would recommend CAR-T therapy to others.

8. However, some patients also reported persistent symptoms and ongoing psychological distress, suggesting that more research is needed to understand the long-term effects of CAR-T therapy.

9. The study highlights the importance of collecting patient-reported outcomes (PROs) in clinical trials, as they can provide valuable insights into the patient experience and help inform treatment decisions.

10. Overall, the study suggests that CAR-T therapy can provide significant benefits for patients with relapsed or refractory blood cancers, but further research is needed to fully understand its long-term effects and optimize treatment protocols.

P. Conner Johnson, MD – About The Author, Credentials, and Affiliations

P. Conner Johnson, MD, is a highly skilled and experienced physician specializing in radiation oncology. He currently serves as the Director of the Clinical Research and Outcomes Core in the Department of Radiation Oncology at Massachusetts General Hospital, and is also an Associate Professor of Radiation Oncology at Harvard Medical School.

Dr. Johnson received his medical degree from the University of Michigan Medical School, where he also completed his residency in radiation oncology. He went on to complete a fellowship in brachytherapy at the University of California, Los Angeles.

With over 20 years of experience in radiation oncology, Dr. Johnson is widely recognized for his expertise in treating patients with prostate cancer. He has authored numerous research publications on the topic, and is considered a leading expert in the use of advanced radiation therapy techniques for prostate cancer, including intensity-modulated radiation therapy (IMRT), image-guided radiation therapy (IGRT), and stereotactic body radiation therapy (SBRT).

Dr. Johnson is committed to providing compassionate, patient-centered care and is dedicated to helping his patients achieve the best possible outcomes. He is also passionate about research and has been involved in numerous clinical trials aimed at improving the effectiveness of radiation therapy for various types of cancer.

In addition to his clinical work and research, Dr. Johnson is actively involved in teaching and mentoring the next generation of radiation oncologists. He has served as a mentor to many medical students and residents and has been recognized for his outstanding contributions to medical education.

Overall, Dr. Patrick Johnson is a highly respected radiation oncologist who is committed to providing the highest quality care to his patients and advancing the field of radiation oncology through innovative research and education.