Chimeric Antigen Receptor (CAR) T-cell Therapy
Summary
The patient's t cells are removed from body, transformed, and readministered back to the patient to fight cancer.
Mainly used to tx hematologic malignancies.
1st generation initiated in 1987. 2nd generation approved in 2017 by FDA. Total 5 therapy products availible, 1 is approved for children (tisagenlecleucel).
Creation of recombinant CAR t-cells from leukopheresis takes about 3-4 weeks. Pt undergoes immune cell depletion prior to infusion.
Intense acute post infusion survilance for life threatening conditions such as CRS, ICANS, ARDS, shock, etc.
Further long term post infusion surveillance includes monitoring for B-cell aplasia, hypogammaglobulinemia, and infections. Patients may require immunoglobulin replacement
therapy and prophylactic antibiotics to prevent infections. Long-term follow-up is essential to manage and mitigate late-onset toxicities and secondary malignancies.
Key Terms
- Recombinant
- Refers to DNA, cells, or organisms that have been engineered to contain genes from different sources, often used to create proteins or receptors with specific functions.
- Cytokine Release Syndrome (CRS)
- Signs and symtoms range from mild flu like sx to severe sx like decompensated shock, ARDS, or multiorgan failure. CRS typically treated with Tocilizumab.
- Immune Effector Cell-associated neurotoxicity syndrome (ICANS)
- ICANS is a neurological toxicity that can occur after CAR T-cell therapy. Symptoms can range from mild confusion and headache to severe seizures, cerebral edema, and coma. Management includes supportive care and corticosteroids.
- GVHD
- Graft vs. Host Disease. T cells from graft (donor) attack the pt's healthy tissue.
Indications
- ABECMA (idecabtagene vicleucel)
- Treatment of adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.
- BREYANZI (lisocabtagene maraleucel)
- Adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
- Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or
- Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age; or
- Relapsed or refractory disease after 2 or more lines of systemic therapy.
- Limitations of Use: BREYANZI is not indicated for the treatment of patients with primary central nervous system lymphoma
- Adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
- Adult patients with relapsed or refractory follicular lymphoma (FL) who have received 2 or more prior lines of systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
- Adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least 2 prior lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor.
- CARVYKTI (ciltacabtagene autoleucel)
- Treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide.
- KYMRIAH (tisagenlecleucel)
- KYMRIAH is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of:
- Patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.
- Adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.
- Limitations of Use: KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma.
- Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
- TECARTUS (brexucabtagene autoleucel)
- TECARTUS is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:
- Adult patients with relapsed or refractory mantle cell lymphoma (MCL). This indication is approved under accelerated approval based on overall response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
- Adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
- YESCARTA (axicabtagene ciloleucel)
- YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:
- Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
- Adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
- Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
- Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.
Contraindications
- Depends on the agent used.
Adverse Effects
- Cytokine Release Syndrome (CRS)
- Immune Effector Cell-associated neurotoxicity syndrome (ICANS)
- ARDS
- multiorgan failure
General Therapy Procedure
- Therapy over several weeks
- T Cell collection via leukapheresis
- Collected T Cells sent to lab
- 2-3 weeks: t cells undergo vector insertion and cellular expansion
- Lentiviruses are used to implant the CAR gene into T cells
- Quality control testing
- t cells are washed and harvested
- Bridging Therapy: if needed, pt undergoes chemotherapy to reduce high cancer burden.
- Immune System Reduction: Usually with lymphodepleting agents like fludarabine and cyclophosphamide, reduce competition for recombinant t cells
- Pt is hospitalized and monitored
- Recombinant T cells are infused back into patient
- Pt is monitored for neuro changes, Cytokine Release Syndrome (CRS), and Immune Effector Cell-associated neurotoxicity syndrome (ICANS) is monitored
MOA
4 Step Mechanism:
- Antigen Recognition and molecular binding
- Intracellular Activation and Signal Transduction
- Cytotoxic Effector Function
- Clonal Expansion and Immunologic Memory
History
Dr. Carl June, MD pioneered the therapy. 1st generation drug was developed in 1987. 2nd generation FDA approved in 2017.
References