CAR T Cell Therapy and Its Cardiovascular Effects

This article was written in collaboration with Dr. Amit Mehta and Dr. Carrie Lenneman.

What is CAR T Cell Therapy?

CAR T or chimeric antigen receptor T cell therapy consists of a recombinant fusion of a protein capable of activating T-cells to recognize a specific antigen resulting in the killing of the cell. It is a new form of immunotherapy that uses specially altered T cells to more specifically target cancer cells. It is a way to boost our immune system to fight cancer and protect our bodies.

The first very successful therapy is the CD19-specific CAR T. CD19 is an effective target since it is expressed through the B-cell lymphocyte lineage development and has a high level of expression on the surface of nearly all B-cell malignancy and is not present on any normal hematological tissue. For this reason, CAR T cell therapy has had remarkable success in highly refractory and relapsing hematological malignancies such as large B-cell lymphoma, multiple myeloma, or acute B-cell lymphoblastic leukemia or ALL.

In a patient population in which curative options are exhausted and where palliative therapy would be the mainstay of therapy, CAR T cell therapy has brought complete remission and survival at 1 year as high as 50% and 76%. It has been used primarily in children with ALL and adults with advanced B-cell lymphoma. Indications of CAR T cell therapy are expected to expand for hematological malignancies and solid tumors.

How is CAR T Cell Therapy Performed?

The T cell lymphocytes are collected from the patient and genetically modified in the laboratory to reprogram those same T cells to recognize the tumor cell. While in the lab, the CAR T cells undergo rapid multiplication to generate therapeutic quantities before being administered back to the same patient by a single intravenous infusion. To prepare the patient for CAR T cell therapy, it is usually necessary to administer chemotherapy to lower their lymphocyte counts. Several different CAR T cell treatments have been approved by the FDA: Breyanzy, Kymriah, Tecartus, and Yescarta, while several other treatments are under investigation.

How Effective Are the Current CAR T Cell Therapies?

One of the most challenging limitations of CAR-T cell therapy is the development of tumor resistance to single antigen targeting CAR constructs. Although initially single antigen targeting CAR-T cells can deliver high response rates, the malignant cells of a significant portion of patients treated with these CAR-T cells may display either partial or complete loss of target antigen expression. This phenomenon is known as antigen escape—or a down-regulation of CD19. ALL patients show durable responses to CD19 targeted CAR-T cell therapy, recent follow-up data suggest the development of a common disease resistance mechanism, including downregulation/loss of CD19 antigen in 30–70% of patients who have recurrent disease after treatment. Similar antigen escape resistance patterns have been observed in solid tumors.

In order to reduce the relapse rate in CAR-T cell treatment of both hematological malignancies and solid tumors, many strategies are now relying on targeting multiple antigens. One of the main causes of no response or weak response to CAR-T cell therapy is poor T cell expansion and short-term T cell persistence. Therefore there are studies looking at the use of immune checkpoint inhibitors (ICIs) (PD-1 or CTLA-4), which can augment T cell expansion, and combining CAR-T with ICIs to help boost response rates.

Cytokine Release Syndrome (CRS) as a Side Effect of CAR T Cell Therapy

A major side effect of any type of immunotherapy, including CAR T cell therapy, is the cytokine release syndrome (CRS). It is a clinical syndrome that occurs in response to a widespread release of inflammatory cytokines and chemokines when large amounts of lymphocytes are activated. Cytokines are small proteins that are important in cell signaling and include growth factors, Interferon, and Interleukins (IL-6) that are involved in inflammation.

Symptoms of CRS can range from mild constitutional symptoms like fever, fatigue, and flu-like illness to severe and life-threatening hypotension and hypoxia leading to confusion, rapid breathing, collapse, and death.

The severity of the syndrome varies according to the disease burden and the dose of CAR T cells infused. It occurs usually between 5-6 days after the infusion and can be categorized into 4 clinical stages:

Grade 1: fever only

Grade 2: fever, mild hypotension, and hypoxia (requiring O2 nasal cannula)

Grade 3: fever, hypotension requiring pressors, and hypoxia on >6 liters O2

Grade 4: fever, hypotension requiring multiple pressors, and severe hypoxia requiring O2 supplement positive pressure

The treatment of low-grade CRS is usually conservative. In severe cases (grades 3 and 4), blockage of interleukin IL-6 with tocilizumab or siltuximab (IL-6 antagonists) is usually necessary. When refractory, high-dose corticosteroids are used.

Management of neurotoxicity focuses on corticosteroids as IL-6 inhibitors are often not effective for neurotoxicity associated with CAR-T cell therapy.

What are the Cardiovascular Effects?

The cardiovascular effects of CAR T cell therapy are not well characterized. Adults receiving CAR T cell treatment represent a particularly at-risk patient population for cardiac injury because of previous exposure to cardiotoxic cancer treatment (anthracycline/radiotherapy) and may have comorbidities. Most of the hemodynamic instability and cardiovascular complications are transient and reversible.

Most of the data on cardiovascular effects of CAR T cell therapy has come from retrospective studies, notably the study of adults with CD19 malignancy treated with this therapy at the University of Pennsylvania between 2010 and 2019. This is where CAR T cell therapy was first performed. A total of 145 patients (36 ALL, 66 CLL, and 43 B-cell lymphomas) were treated. CRS occurred in 104 patients (72%) within 6 days of infusion. Major adverse cardiac events (MACE) occurred in 31 patients within 11 days of infusion, all of which had to precede CRS (grade 3-4). Among patients who had a MACE, 22 had congestive heart failure (1 Takotsubo), 12 atrial fibrillation, 2 acute coronary syndromes, and 2 cardiac deaths.

From a perspective standpoint, 80% of patients who undergo CAR T cell therapy survive at 6 months and 71% are alive at 1 year. Fifteen percent develop heart failure. This is considerably higher than the 4% seen after anthracycline treatment for lymphoma.

In a registry of 137 patients who underwent CD19 T cell therapy, cardiovascular events were 1.7 fold higher for each 12 hr delay in the administration of Tocilizumab for CRS.

It is possible to implicate chemokines such as IL-6 as a possible reason for developing heart failure since it is a similar situation to sepsis or stress. Another mechanism could involve direct cardiotoxicity due to cross-reactivity with unrelated protein or autoimmunity with off-target cross reactivity.

How Do We Mitigate the Risk of Cardiovascular Events Post CAR T Cell Therapy?

Prospective studies are needed to establish the optimal treatment planning for CAR T cell therapy in adults. All patients should be evaluated for previous exposure to chemotherapy and radiation, 12 lead ECG, baseline cardiac function by 2D echocardiography, cardiac markers (troponin and NT-proBNP), high-risk CAD should probably undergo cardiac CT for calcium score, and CTA or MRI if needed.

After CAR T cell infusion, ECG, biomarkers, and echo should be performed and patients should be followed by cardio-oncology.