CAR T-cell therapy, together with checkpoint inhibition, has shown promising results in the clinic. Immunotherapy treatments stimulate the body’s immune system to fight cancer. When the immune system is functioning normally, immune cells move throughout the body, searching for “invaders” to destroy. Most cancer cells, however, can hide from these immune cells, which is why they grow out of control.
In CAR T-cell therapy, clinicians reprogram patients’ own immune cells to find and destroy cancer cells. Clinicians remove patients’ T cells, genetically change them in the lab to attack cancer cells and inject them back into the patients’ body. CAR T-cell therapy is considered a “living therapy” because the cells multiply in the body and sustain their effectiveness over time, so they only have to be injected once.
For these therapies to be undertaken, patients must have T cells on which to perform this genetic engineering. As of mid-2018, CAR T-cell therapies are currently mainly used for liquid tumors. Novartis’ drug Kymriah was approved by the FDA for numerous lymphomas on May 1, 2018. Kymriah is the only CAR-T therapy that is FDA-approved for two distinct indications – in non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL). In the clinic, it demonstrated an overall response rate of 50%, with median duration of response not yet reached at the time of data cut-off, indicating sustainability of response.
More than 200 CAR T-cell clinical trials have been initiated so far, most of which aim to treat lymphoma or leukemia patients. More focus is being directed to solid tumors, but not all of these studies have shown promising results to-date.
CAR T-cell therapy causes the body to release a large quantity of cytokines when the cells activate the immune system. This can cause a number of side effects, including high fevers, low blood pressure and poor lung oxygenation.
In a few patients, CAR T-cell therapy resulted in severe adverse events with a fatal outcome. Thus, it’s critical for clinical operations teams to understand how to identify, treat and also prevent these SAEs during a study.
Other serious side effects include:
These side effects can be life-threatening, so it’s critical for patients in any CAR T-cell study to know what to watch for and communicate with the CRAs and cancer care team. It’s also critical for the CRO or study management team to have the proper education and procedures in place to be able to recognize and treat these before they become life-threatening.
Since we’re in the early stages of studying CAR T-cell therapies in the clinic, many sites, CROs and clinical operations folks are still learning about the best approaches for keeping patients safe. As immunotherapy treatments become more prevalent, clinical teams will become more accustomed to handling the side effects.
From our experience managing numerous CAR T-cell therapy studies (and other immunotherapy treatments), the most effective procedure for mitigating side effects in CAR T-cell therapies includes the following steps:
While this may sound like a standard operation procedure, in many instances, it’s not the norm in the early stages of new research. Because there’s a learning curve for sites, CROs and sponsors, selecting a site with experience in immunotherapies and CAR T-cell studies is the first step. This relieves the burden of training the site from scratch. Turnover is common at sites, so comprehensive training, even for experienced sites, is critical.
Once the site training is complete, the next step is to establish the communication plan. The execution of this plan is the most critical element of the entire procedure:
Continually, and effectively, communicate with the team throughout the study
At Medelis, we introduce the communication plan at the first site initiation visit. We complete detailed training with all members of the site, even with sites that have experience running CAR T-cell studies. If coordinators are new nurses, they may not be familiar with all of the potential side effects. While the PI will speak with the nurses, the nurse is the frontline, so working directly with nurses is important.
Communication with the nurses is an ongoing process, not a one-and-done process (like some big CROs use). We meet with the site before the initial infusions to coach them through the side effects. We hold continuing team meetings with site physicians and coordinators, so we can debrief and help to anticipate what may happen with other patients. From our experience, this constant communication process does improve safety.
For every study, we:
This last point isn’t common in all studies, but it’s important, because at times coordinators aren’t that forthcoming in group calls / phone meetings due to a fear of not wanting to sound “dumb” in front of their colleagues. It’s human nature. One-on-one communication allows them to ask the important questions.
Rigorous communication enables us to detect problems early. It helps to reduce deviations. For example, we had an SAE in one of our CAR T-cell studies last week: a patient contracted hypoxia due to the drug. The patient had lung cancer and some hypotension, and the question was this: Did the lung cancer exacerbate the SAE, or was it the other way around? The communication plan enabled the team to determine the result.
With cytokine release syndrome, we often speak to a research nurse and ask them about their pre-med cocktail, researching on PubMed and evaluating the risk / benefit ratio to determine if it’s in balance. Moreover, sharing the collective experiences across the organization speeds the learning curve. We’re managing a number of CAR T-cell studies and update SOPs with new learnings. For example, one of our current studies is utilizing a novel approach of laparoscopy into the abdomen to treat malignant ascites. The PI is an innovator, and it requires new and specific training and techniques.
Overall, these therapies are very promising. A continued sharing and updating of operational SOPs will help to increase safety and possibly contribute to better study outcomes.
Connect with us if you’d like to discuss your upcoming CAR T-cell study.