Straight Dope on Medicine: CAR-T Magic Wand

Author

Scott Ganser
December 11, 2023

Car-T is a medical magic wand. With it, scientists can do virtually anything.

Some describe it as a “living drug.”

Invented in the Perelman School of Medicine at University of Pennsylvania by Carl June, MD, the Richard W. Vague Professor in Immunotherapy, CAR T cell therapy works by collecting T cells from a patient, modifying those cells in the lab so that they are designed to destroy cancerous cells, and reinfusing them into the patient. June’s research led to the first FDA approval for this type of therapy, in 2017. Six different CAR T cell therapies are now approved to treat various types of blood cancers.[i]

Some estimate that 80% of ALL cancers will be eventually cured by CAR-T.

In 2017, two chimeric antigen receptor-T (CAR-T) therapies were approved by the FDA for advanced/resistant lymphoma and acute lymphoblastic leukemia. However, despite the breakthrough efficacy results, the safety of CAR-T treatment is still a concern for treating physicians and their patients.

We found that the CAR T cells survived in some of the first patients treated – back in 2010 – for more than a decade. So, we can really say CAR T cells are a living drug. CAR T cell therapy has exquisite selectivity for blood cancers— meaning it does a good job of only attacking cancer cells— and because it doesn’t affect healthy cells, it doesn't cause the same side effects chemotherapy does. That that's been a major paradigm shift.

Beyond cancer, we’re seeing early signs that CAR T cell therapy could work in autoimmune diseases, like lupus. In lupus, immune cells target the patient’s own DNA, creating antibodies against their DNA, which leads to tissue damage. CAR T cell therapy could be used to target the cells that make those autoimmune antibodies and kill them, which should resolve the tissue damage. And that's exactly what the early trials are showing.

There have been clinical reports in other autoimmune diseases, including myasthenia gravis and inflammatory myopathy.

Not Perfect

At least, not yet.

the relapse in up to 60% of patients and certain side effects such as cytokine release syndrome (CRS). The key cytokine for CRS is IL-6, which is the main cause of the immune reactions of CRS such as fever, chills, headache, and malaise. Neurologic toxicities were also reported. This led to extensive clinical activities aimed at overcoming these obstacles, so that the use of CAR-T therapy can be expanded.

Addition of other agents was the thinking.

Combining it with chemotherapy, and the development of next-generation CAR-T therapies, e.g., through the use of CAR-natural killer (CAR-NK) and CAR macrophages (CAR-Ms).[ii] 

To date, there are six approved CAR-T products. Four target CD19 and the other two BCMA.

There was a high response rate in difficult to treat conditions with no alternatives.

One of the words being tossed around is “unprecedented.”

CAR-T cells are one of the most advanced immunotherapeutic approaches for patients with r/r B cell non-Hodgkin lymphoma (B-NHL) that resisted multiple chemotherapies and/or HSCT In a phase I/II clinical trial, Turtle and colleagues evaluated the efficiency and safety of adoptive CD19 CAR-T cell therapy in patients with advanced CD19 + B cell malignancies, including NHL. They observed that the overall response rate for patients who received CAR-T cells after lymphodepletion was 84%, in which 47% of the patients experienced CR (complete remission).[iii]

A phase 1 long-term cohort study conducted at the Memorial Sloan Kettering Cancer Center in 53 adult patients (median age, 44 y) with relapsed B-ALL showed that autologous CAR-T cells therapy led to a complete remission (CR) rate of 83% with a median overall survival (OS) of 12.9 months (95% CI 8.-23.4).

T Cell Malignancy

A potential drawback has emerged. It is difficult to say whether or not this is legitimate. The FDA does NOT like cell therapies. That is why they have virtually no approved stem cell therapies after 20 years, though it has been proven they work.

The FDA is now weighing potential regulatory action—even as the potential risk of developing secondary cancer is already included as a class warning on the labels of the CAR-T therapies.

Currently marketed CD19 CAR-Ts include Yescarta and Tecartus from Gilead Sciences’ Kite Pharma, Novartis’ Kymriah and Bristol Myers Squibb’s Breyanzi. Johnson & Johnson and Legend Biotech’s Carvykti is a competitor to BMS’ Abecma in the BCMA space. A search of the FDA’s adverse events reporting system showed T-cell lymphoma cases for Breyanzi, Carvykti, Kymriah and Yescarta.[iv]

In a statement to Fierce Pharma, a Gilead spokesperson said the company is “confident in the overall safety profile of both Tecartus and Yescarta.” The sister therapies have so far reached 17,700 patients, with no evidence to date that suggests a causal role linking them with the development of new malignancies, the spokesperson added. 

“We have a rigorous process in place to continuously monitor for and report adverse events to regulatory authorities,” the Gilead representative said. “We have fully cooperated with the FDA’s request for an analysis of our data related to this inquiry.”  

For Kymriah, Novartis also expressed confidence in its CD19 offering’s benefit-risk profile. With more than 10,000 patients treated, Novartis has not identified a causal relationship between Kymriah and secondary malignancies, the company said in a separate statement.

BMS noted that among the 4,700 patients it has treated with Abecma or Breyanzi, none developed CAR-positive T-cell malignancy. The company is responding to the FDA’s requests for information, a BMS spokesperson said, and it remains confident in the safety profile and clinical value of its cell therapies.

 

Autoimmune Diseases

This is a bit further behind, but it does count as a work in development.[v]

Lupus is furthest along. Let’s check it out.

Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease characterized by adaptive immune system activation, formation of double-stranded DNA autoantibodies and organ inflammation. Five patients with SLE (four women and one man) with a median (range) age of 22 (6) years, median (range) disease duration of 4 (8) years and active disease (median (range) SLE disease activity index Systemic Lupus Erythematosus Disease Activity Index: 16 (8)) refractory to several immunosuppressive drug treatments were enrolled in a compassionate-use chimeric antigen receptor (CAR) T cell program. 

CAR T cells expanded in vivo, led to deep depletion of B cells, improvement of clinical symptoms and normalization of laboratory parameters including seroconversion of anti-double-stranded DNA antibodies. Remission of SLE according to DORIS criteria was achieved in all five patients after 3 months and the median (range) Systemic Lupus Erythematosus Disease Activity Index score after 3 months was 0 (2). Drug-free remission was maintained during longer follow-up (median (range) of 8 (12) months after CAR T cell administration) and even after the reappearance of B cells, which was observed after a mean (±s.d.) of 110 ± 32 d after CAR T cell treatment.[vi]

Myasthenia gravis is characterized by rogue antibodies that go after the neuromuscular junction. This is the immune equivalent of “killed by friendly fire.”

The first study to use an RNA-based chimeric antigen receptor T-cell (rCAR-T) therapy in autoimmune disease showed people with generalized myasthenia gravis tolerated the treatment well and experienced improvements in disease severity scales.

In the phase Ib/II, no study-related serious adverse events or cases of dose-limiting toxicity, cytokine release syndrome, or neurotoxicity emerged in any of 14 participants, reported James Howard Jr., MD, of the University of North Carolina in Chapel Hill, and co-authors.[vii]

 

Although four participants developed fevers, all resolved within 24 hours of infusion and were not associated with cytokine release syndrome, the researchers wrote in Lancet Neurologyopens.

Mean improvements from baseline to week 12 were seen on four validated scales, including:

  • 6 points on Myasthenia Gravis-Activities of Daily Living (MG-ADL) score

  • 7 points on Quantitative Myasthenia Gravis (QMG) score

  • 14 points on Myasthenia Gravis Composite (MGC) score

  • 9 points on Myasthenia Gravis Quality of Life 15-revised (MG-QoL-15r) score

 


[ii] Chen YJ, Abila B, Mostafa Kamel Y. CAR-T: What Is Next? Cancers (Basel). 2023 Jan 21;15(3):663. doi: 10.3390/cancers15030663. PMID: 36765623; PMCID: PMC9913679.

[iii] Dagar, G., Gupta, A., Masoodi, T. et al. Harnessing the potential of CAR-T cell therapy: progress, challenges, and future directions in hematological and solid tumor treatments. J Transl Med 21, 449 (2023). https://doi.org/10.1186/s12967-023-04292-3

[v] Bao L, Bo XC, Cao HW, Qian C, Wang Z, Li B. Engineered T cells and their therapeutic applications in autoimmune diseases. Zool Res. 2022 Mar 18;43(2):150-165. doi: 10.24272/j.issn.2095-8137.2021.363. PMID: 35008131; PMCID: PMC8920845.

[vi] Mackensen, A., Müller, F., Mougiakakos, D. et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 28, 2124–2132 (2022). https://doi.org/10.1038/s41591-022-02017-5