33 Adoptive Cellular Therapy

Question 1

What have cellular therapies broadened for patients?

Answer 1

Therapeutic options for patients with hematologic malignancies and solid tumors.

Question 2

Which chimeric antigen receptor T (CAR T) cells are FDA-approved for relapsed or refractory hematologic malignancies?

Answer 2

CAR T cells targeting either CD19 or BCMA.

Question 3

From which sources can CAR T cells be engineered?

Answer 3

Autologous or allogeneic cell sources.

Question 4

How do CAR T cells engage antigens compared to T-cell receptor (TCR) T cells?

Answer 4

CAR T cells engage the cognate antigen in a major histocompatibility complex (MHC)–independent manner.

Question 5

What do TCR T cells recognize?

Answer 5

Antigen presented by MHC on antigen-presenting cells.

Question 6

What are the on-target, off-tumor side effects that can occur after CAR T-cell therapy?

Answer 6

• Cytokine release syndrome (CRS) * Immune effector cell-associated neurotoxicity syndrome (ICANS) * Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS)

Question 7

What does adoptive cellular therapy encompass?

Answer 7

Treatment that harnesses the transfer of immune cells to treat infections or cancer.

Question 8

What insights have current therapies leveraged that date back several decades?

Answer 8

• Tumor-infiltrating lymphocytes (TILs) * Chimeric antigen receptor T (CAR T) cells * Allogeneic hematopoietic cell transplantation (HCT)

Question 9

What significant progress has been made in cellular therapies?

Answer 9

Substantial preclinical and clinical progress that may benefit patients.

Question 10

What will be excluded from the subsequent discussion on cellular therapy?

Answer 10

Allogeneic hematopoietic cell transplantation (HCT).

Question 11

What is a chimeric antigen receptor (CAR)?

Answer 11

A recombinant receptor consisting of an extracellular single-chain variable fragment of an antibody, a spacer or hinge region, the T-cell receptor (TCR) CD3z chain, and a costimulatory domain.

Question 12

What limitation did the first-generation CAR have?

Answer 12

Limited in vivo expansion, persistence, and antitumor activity.

Question 13

What is the main improvement in the second generation of CAR T cells?

Answer 13

Incorporation of a costimulatory domain (e.g., CD28, 4-1BB, OX40).

Question 14

What distinguishes CAR T cell activation from endogenous T cell activation?

Answer 14

CAR T cells bind to their target antigen in a human leukocyte antigen-independent manner.

Question 15

How can CAR T cells be introduced into T cells?

Answer 15

Through retroviral or lentiviral transduction or via electroporation of CAR-encoded messenger RNA constructs.

Question 16

What is the purpose of lymphodepleting chemotherapy before CAR T cell infusion?

Answer 16

To facilitate in vivo expansion of CAR T cells by removing regulatory T cells and generating a supportive cytokine milieu.

Question 17

How many CAR T-cell products are currently approved by the FDA?

Answer 17

Seven CAR T-cell products.

Question 18

What are the categories of approved CAR T-cell products?

Answer 18

• 5 CD19-targeted therapies
• 2 B-cell maturation antigen (BCMA)–directed CAR T-cell products.

Question 19

What is a major characteristic of all approved CAR T-cell products?

Answer 19

They are indicated in the relapsed/refractory setting.

Question 20

What is the primary manufacturing method for traditional CAR T cells?

Answer 20

Using autologous cells isolated from patients via leukapheresis.

Question 21

What is a significant drawback of autologous CAR T cell therapy?

Answer 21

It is time-consuming and costly, and not feasible for all patients due to prior therapy damage.

Question 22

What are allogeneic CAR T-cell products?

Answer 22

Donor-derived CAR T-cell products that can be administered ‘off the shelf’.

Question 23

What gene editing methods are commonly used for allogeneic CAR T-cell products?

Answer 23

• CRISPR
• Transcription activator-like effector nucleases.

Question 24

How do TCR-engineered T cells differ from CAR-modified T cells?

Answer 24

TCR-engineered T cells recognize antigens presented by MHC, while CAR T cells recognize cognate antigens in an MHC-independent manner.

Question 25

What is a key challenge in TCR T-cell therapy?

Answer 25

The risk of off-target autoimmunity due to potential mispairing with endogenous TCR chains.

Question 26

What are the main advantages of NK cells in therapy?

Answer 26

They do not require prior antigen sensitization and do not cause GVHD in the allogeneic setting.

Question 27

What is the typical source for allogeneic NK cells?

Answer 27

Peripheral blood or umbilical cord blood products.

Question 28

What type of chemotherapy can facilitate NK-cell persistence and expansion?

Answer 28

Lymphodepleting chemotherapy with cyclophosphamide and fludarabine.

Question 29

What are tumor-infiltrating lymphocytes (TILs)?

Answer 29

Autologous T cells collected from resected tumor material, expanded ex vivo, and infused back into the patient.

Question 30

What is the role of IL-2 in TIL therapy?

Answer 30

To improve antitumor activity.

Question 31

What is a notable challenge associated with TIL therapy?

Answer 31

The need to surgically remove tumor material from each patient before isolation of TILs.

Question 32

What is the FDA-approved TIL product mentioned in the text?

Answer 32

Lifileucel, indicated for adult patients with unresectable or metastatic melanoma.

Question 33

What is cytokine release syndrome (CRS)?

Answer 33

A systemic inflammatory response following CAR T-cell infusion characterized by mild to severe symptoms ## Footnote CRS is associated with cytokines like IFN-γ, TNF-α, and IL-6 released during the antitumor response.

Question 34

What are common side effects of CD19-directed CAR T-cell therapy?

Answer 34

Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), and B-cell aplasia ## Footnote These side effects can range from mild to life-threatening.

Question 35

What symptoms characterize CRS?

Answer 35

Low-grade constitutional symptoms such as fever and flu-like symptoms to high-grade syndrome with hypotension, lung injury, and multiorgan dysfunction ## Footnote CRS symptoms can vary significantly in severity.

Question 36

What treatments are available for CRS?

Answer 36

Symptomatic/supportive treatments, vasopressors, blood product transfusions, mechanical ventilation, tocilizumab, and corticosteroids ## Footnote Tocilizumab is an IL-6 receptor antagonist that can abrogate CRS without hindering antitumor response.

Question 37

What is immune effector cell-associated neurotoxicity syndrome (ICANS)?

Answer 37

A common side effect of CAR T-cell therapy characterized by neurological symptoms ranging from delirium to life-threatening complications ## Footnote ICANS can occur concurrently with or after CRS.

Question 38

What are some neurological symptoms of ICANS?

Answer 38

Delirium, dysphasia, akinetic mutism, headache, aphasia, tremor, seizure, somnolence, and cerebral edema ## Footnote While largely reversible, ICANS can lead to fatal cerebral edema in some cases.

Question 39

What factors are associated with higher rates of neurotoxicity in CAR T-cell therapy?

Answer 39

High tumor burden and increased depth of lymphodepletion ## Footnote These factors serve as predictors but complications remain difficult to predict.

Question 40

What is immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS)?

Answer 40

A CAR-mediated toxicity presenting with symptoms like hemophagocytic lymphohistiocytosis due to macrophage activation ## Footnote IEC-HS is distinct from CRS and ICANS but can present with fever, hypotension, and hypoxia.

Question 41

What organization published consensus definitions and grading systems for CRS and neurotoxicity in 2018?

Answer 41

The American Society of Transplantation and Cell Therapy ## Footnote These definitions provide standardized criteria for assessing CRS and ICANS severity.

Question 42

How is CRS graded?

Answer 42

Based on the presence of fever and the degree of hypoxia and hypotension ## Footnote This grading system helps in the clinical assessment of CRS severity.

Question 43

How is ICANS graded?

Answer 43

Based on the presence of neurologic findings and the ability to answer questions as part of the ICANS score ## Footnote This grading incorporates cognitive assessment as a component.

Question 44

True or False: The treatment-related mortality of CAR T-cell therapy is higher than that of autologous transplant.

Answer 44

False ## Footnote Treatment-related mortality for CAR T-cell therapy is similar to that of autologous transplant.

Question 45

What is the potential outcome of IEC-HS in patients?

Answer 45

It can lead to symptoms similar to hemophagocytic lymphohistiocytosis due to macrophage activation ## Footnote IEC-HS is a distinct toxicity that requires careful monitoring.

Question 46

Fill in the blank: The cytokines implicated in CRS include _______.

Answer 46

IFN-γ, TNF-α, IL-6 ## Footnote These cytokines play a significant role in the inflammatory response during CAR T-cell therapy.

Question 47

What are the mid- to long-term side effects of CAR T-cell therapy?

Answer 47

Cytopenia and the risk of secondary malignancies, including T-cell lymphomas ## Footnote Investigators are assessing the incidence and mechanism of these long-term side effects as more data are collected.

Question 48

What response rates have been reported for CD19-directed CAR T cells in B-cell acute lymphoblastic leukemia?

Answer 48

Approximately 80% to 90% ## Footnote These rates apply to both pediatric and adult patients with relapsed B-ALL.

Question 49

What is the name of the first CAR T-cell therapy approved by the FDA?

Answer 49

Tisagenlecleucel (tisa-cel, CTL019) ## Footnote It was approved based on results from the ELIANA trial.

Question 50

What was the overall remission rate for patients receiving tisagenlecleucel in the ELIANA trial?

Answer 50

81% ## Footnote All patients were measurable residual disease negative.

Question 51

What are the 12-month event-free survival (EFS) and overall survival (OS) estimates for patients treated with tisagenlecleucel?

Answer 51

EFS: 50%, OS: 76% ## Footnote These estimates reflect the outcomes from the ELIANA trial.

Question 52

What percentage of patients experienced CRS while receiving CAR T-cell therapy?

Answer 52

77% ## Footnote 48% of these patients required tocilizumab for management.

Question 53

What complications delayed the approval of anti-CD19 CAR T-cell therapy for adult patients with B-ALL?

Answer 53

Cerebral edema and refractory CRS leading to death ## Footnote These complications were noted in early clinical trials.

Question 54

What was the complete response (CR) rate reported by the University of Pennsylvania for adult patients receiving anti-CD19 CAR T cells?

Answer 54

90% ## Footnote This was observed in a study involving high-dose CAR T cells.

Question 55

What was the completion response rate and median duration of response for the ZUMA-3 study in adult B-ALL patients?

Answer 55

CR rate: 71%, Median duration of response: 12.8 months ## Footnote This study led to FDA approval for relapsed/refractory adult B-ALL.

Question 56

What percentage of patients in the ZUMA-3 study experienced CRS?

Answer 56

89% ## Footnote Grade 3 to 4 CRS occurred in 24% of patients.

Question 57

What is the second approved CAR T-cell therapy for adults with relapsed/refractory large B-cell lymphoma?

Answer 57

Axicabtagene ciloleucel (axi-cel) ## Footnote Approved for treatment after 2 or more lines of systemic therapy.

Question 58

What was the overall response rate in the ZUMA-1 trial for axicabtagene ciloleucel?

Answer 58

82% ## Footnote The complete response rate was 54%.

Question 59

What are the common grade 3+ events associated with axicabtagene ciloleucel treatment?

Answer 59

Neutropenia, anemia, and thrombocytopenia ## Footnote CRS and neurologic events also occurred in a significant percentage of patients.

Question 60

What notable outcomes were found in the ZUMA-7 study for axi-cel as second-line treatment?

Answer 60

Improved OS compared to standard care with autologous HCT ## Footnote This was demonstrated in patients with relapsed/refractory LBCL.

Question 61

What is the best overall response rate for tisa-cel in the JULIET trial?

Answer 61

52% ## Footnote 40% of patients achieved a complete response.

Question 62

What distinguishes lisocabtagene maraleucel (liso-cel) from other CAR T-cell therapies?

Answer 62

Administered as 2 doses with a fixed ratio of CD4+ and CD8+ CAR T cells ## Footnote It is also an anti-CD19, 4-1BB CAR T-cell product.

Question 63

What was the overall response rate for liso-cel in the TRANSCEND trial?

Answer 63

73% ## Footnote The complete response rate was 53%.

Question 64

What is the FDA approval status of liso-cel?

Answer 64

Approved as a second-line indication for adults with LBCL ## Footnote Applicable for those refractory to first-line therapy or not eligible for autologous HCT.

Question 65

What are the approved indications for tisa-cel compared to axi-cel and liso-cel?

Answer 65

Tisa-cel is only approved as a third-line indication ## Footnote Axi-cel and liso-cel are approved in the second-line context.

Question 66

What is the overall response rate of CD19 CAR T cells in the phase 2 ZUMA-5 clinical trial for chemorefractory FL?

Answer 66

91% ## Footnote This trial also reported a complete response (CR) rate of 61% and 74% of patients remained in remission at 18 months.

Question 67

What were the rates of grade 3+ CRS and neurotoxicity in patients treated with CD19 CAR T cells in the ZUMA-5 trial?

Answer 67

* Grade 3+ CRS: 8% * Neurotoxicity: 21% ## Footnote These adverse effects are significant considerations in the treatment outcomes.

Question 68

What is the overall response rate of Tisa-cel in the ELARA study for follicular lymphoma?

Answer 68

86% ## Footnote The complete response (CR) rate was reported at 69%.

Question 69

What were the grade 3+ toxicity rates for CRS and ICANS in the ELARA study?

Answer 69

* Grade 3+ CRS: 48% * ICANS: 4% ## Footnote These toxicity rates indicate a higher incidence compared to other CAR T therapies.

Question 70

What is brexucabtagene autoleucel (brexu-cel) used for?

Answer 70

Treatment of relapsed/refractory mantle cell lymphoma (MCL) ## Footnote It is a CAR product identical to axi-cel but manufactured differently.

Question 71

What were the overall response rate (ORR) and complete response (CR) rate for brexu-cel in clinical trials?

Answer 71

* ORR: 93% * CR rate: 67% ## Footnote These rates were observed in a phase 2 study with 68 patients.

Question 72

What were the 12-month progression-free survival (PFS) and overall survival (OS) rates for brexu-cel?

Answer 72

* 12-month PFS: 61% * 12-month OS: 83% ## Footnote These metrics reflect the effectiveness of brexu-cel over time.

Question 73

What were the rates of grade 3+ CRS and neurotoxicity in patients treated with brexu-cel?

Answer 73

* Grade 3+ CRS: 15% * Neurotoxicity: 31% ## Footnote These adverse effects are critical in evaluating the safety profile of brexu-cel.

Question 74

What does BCMA stand for in the context of CAR T-cell therapies for multiple myeloma?

Answer 74

B-cell maturation antigen ## Footnote BCMA is targeted by various CAR T-cell therapies in the treatment of multiple myeloma.

Question 75

What is the ORR and CR rate for idecabtagene vicleucel (ide-cel) in relapsed/refractory multiple myeloma?

Answer 75

* ORR: 73% * CR rate: 33% ## Footnote These results were derived from a multicenter phase 2 clinical trial.

Question 76

What percentage of patients experienced CRS and grade 3+ toxicities with ide-cel?

Answer 76

* CRS: 84% * Grade 3+ toxicities: 5% ## Footnote This indicates a high incidence of CRS with relatively low severe toxicity.

Question 77

What are the ORR and stringent CR rate for ciltacabtagene autoleucel (cilta-cel) in multiple myeloma?

Answer 77

* ORR: 94.8% * Stringent CR rate: 56% ## Footnote These results were observed in a phase 2 clinical trial involving 97 patients.

Question 78

What were the 6-month PFS and OS rates for cilta-cel?

Answer 78

* 6-month PFS: 87.4% * 6-month OS: 93.8% ## Footnote These rates highlight the efficacy of cilta-cel in the treatment of multiple myeloma.

Question 79

What were the rates of CRS and neurotoxicity in patients treated with cilta-cel?

Answer 79

* CRS: 95% * Neurotoxicity: 21% ## Footnote The high CRS rate is notable among patients receiving this therapy.

Question 80

As of April 2024, for what treatment line has cilta-cel been approved for multiple myeloma?

Answer 80

Second-line treatment ## Footnote Approval came as part of the CARTITUDE-4 study.

Question 81

What remains a barrier to achieving curative outcomes with CAR T-cell therapies in multiple myeloma?

Answer 81

Relapse ## Footnote Despite high response rates, relapse continues to pose a challenge.

Question 82

What is the focus of ongoing research in cellular therapy for hematologic malignancies and solid tumors?

Answer 82

Identifying novel targets ## Footnote The goal is to improve therapeutic efficacy compared to currently approved therapies.

Question 83

True or False: Hematologists need to be aware of potential previously unidentified toxicities due to new therapies.

Answer 83

True ## Footnote Awareness of toxicities is crucial as new therapies are developed.