CAR T-Cell Therapy in B-ALL Patients

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Questions and Answers

What is the main mechanism of action for the 19-28z CAR modified T cells used in the treatment?

Direct targeting of CD19 expressing tumor cells (correct)

Inhibition of tumor cell growth

Induction of apoptosis in healthy cells

Blocking cytokine signaling pathways

What was the outcome for patients with persistent morphological disease after T cell infusion?

No significant change in tumor size

Increased tumor burden

Only partial remissions were observed

Rapid tumor eradication and MRD-negative complete remissions (correct)

What side effects were observed in patients receiving CAR modified T cell therapy?

Severe neurological disorders

Persistent vomiting and diarrhea

Increased risk of infections

Significant cytokine elevations (correct)

How did cytokine elevations relate to patients' conditions during therapy?

They correlated with tumor burden at the time of infusion Signup and view all the answers

What criteria was met by patients who experienced cytokine-mediated toxicities?

They required lymphotoxic steroid therapy Signup and view all the answers

What potential clinical benefit was suggested for patients experiencing relapse after CAR modified T cell therapy?

Further CAR modified T cell infusions may still have efficacy Signup and view all the answers

What is a potential ideal bridge towards curative therapy following CAR modified T cell therapy?

Autologous stem cell transplantation Signup and view all the answers

What type of cancer is primarily addressed by the therapy involving the 19-28z CAR modified T cells?

B-cell acute lymphoblastic leukemia (B-ALL) Signup and view all the answers

Which patient had the highest total number of IgH rearrangements recorded?

ALL04 Signup and view all the answers

What is the total number of malignant IgH rearrangements for patient MSK- recorded on Day -1?

3,300,732 Signup and view all the answers

Which patient has no recorded malignant IgH rearrangements on Day 30?

ALL03* Signup and view all the answers

On Day 39, how many total IgH rearrangements did patient ALL06 have?

1,866,851 Signup and view all the answers

Which of the following patients had a total of 0 malignant IgH rearrangements recorded?

ALL05* Signup and view all the answers

What does achieving MRD− status improve for patients undergoing treatment?

Bridge to allo-HSCT under optimal conditions Signup and view all the answers

Which factor correlates with cytokine-mediated toxicities during CAR T cell therapy?

Tumor bulk at the time of infusion Signup and view all the answers

What is essential for optimal anti-tumor efficacy according to the findings?

Sufficient persistence of CD19-targeted CAR-modified cells Signup and view all the answers

In what setting does CAR modified T cell therapy show an improved side-effect profile?

In the MRD− setting or after salvage chemotherapy Signup and view all the answers

What was notable about two patients in the cohort without CAR modified T cell therapy?

They were not eligible for allo-HSCT Signup and view all the answers

What does the introduction of CAR modified T cell therapy provide for B-ALL patients?

Increased chances of receiving allo-HSCT in better conditions Signup and view all the answers

What does the study suggest about T cell-mediated cytokine release syndrome?

It does not need to be present for effective CAR T cell action Signup and view all the answers

What is a risk for patients if CAR modified T cell therapy is administered with a high tumor load?

Increased incidence of cytokine-mediated toxicities Signup and view all the answers

What characteristic was found in the relapsed B-ALL tumor cells of the first patient discussed?

Hyperdiploid with an extra copy of the MLL gene Signup and view all the answers

What treatment did the first patient receive after being leukapheresed?

High-dose cytarabine and mitoxantrone Signup and view all the answers

What was the MRD status of the second patient before undergoing an allo-HSCT?

MRD-negative with complete remission Signup and view all the answers

Which complication did the second patient develop after treatment and before her allo-HSCT?

Small bowel obstruction leading to bowel resection Signup and view all the answers

What was the dose of cyclophosphamide administered to both patients prior to T cell infusion?

1.5 gm/m2 Signup and view all the answers

What was the primary goal of the second patient's treatment after her relapse?

To induce a second complete remission (CR2) Signup and view all the answers

What genetic abnormality was noted in the first patient's relapsed tumor cells?

Homozygotic deletion of the p16 gene Signup and view all the answers

How long after the last maintenance treatment did the second patient relapse?

9 months Signup and view all the answers

What type of cells were obtained from patients for the generation of 19-28z CAR modified T cells?

Peripheral blood mononuclear cells (PBMCs) Signup and view all the answers

Which method was used to activate T cells during the production of CAR modified T cells?

Dynabeads® Human T-Activator CD3/CD28 magnetic beads Signup and view all the answers

What was used to assess the persistence of 19-28z CAR modified T cells?

FACS using biotinylated goat anti-mouse IgG F(ab)2 Signup and view all the answers

What type of samples were assessed to monitor the persistence of normal B cells and B-ALL clones?

Bone marrow (BM) and peripheral blood Signup and view all the answers

Which technique was utilized for analyzing tumor and normal B cells in samples?

Flow cytometry Signup and view all the answers

What type of DNA analysis was performed for deep sequencing?

Multiplex PCR and re-sequencing Signup and view all the answers

How were transduced T cells further expanded after modification?

Using a Wave bioreactor Signup and view all the answers

What type of cells are identified as B-ALL clones in the assessment?

CD19+ CD10+ cells Signup and view all the answers

Study Notes

Autologous T Cell Therapy in B-ALL

Five patients with relapsed B-ALL received autologous T cells modified with a CD19-specific dual-signaling CAR (19-28z).
All patients with either persistent morphological disease or minimal residual disease (MRD+) at the time of T cell infusion experienced rapid tumor eradication and achieved MRD-negative complete remissions.
Infusion of CAR-modified T cells was well tolerated, although significant cytokine elevations were observed in patients who had active disease, necessitating lymphotoxic steroid therapy.
Cytokine levels correlated directly with tumor burden at the time of CAR T cell infusion; lower tumor burden resulted in an improved side-effect profile.
One patient, relapsed post-CAR therapy and ineligible for additional allogeneic hematopoietic stem cell transplant (allo-HSCT), showed persistent expression of CD19 and sensitivity to the CAR-modified T cells, indicating potential for additional CAR infusions.

Efficacy and Safety of 19-28z CAR T Cells

The therapy demonstrated marked anti-tumor efficacy, rapidly achieving MRD-negative status, which improves prognosis by making patients eligible for allo-HSCT.
Without CAR therapy, two patients would have been ineligible for transplantation, while another two would have proceeded with poor prognosis due to remaining MRD.
Cytokine-mediated toxicities, previously a concern, were minimized by infusing T cells in patients with lower disease burden either in MRD+ setting or soon after initial salvage chemotherapy.

Treatment Protocol and Patient Cases

Patients underwent leukapheresis to obtain peripheral blood mononuclear cells (PBMCs), which were activated and transduced with the 19-28z receptor using dynabeads.
Two patient case highlights:
- MSK-ALL01: A patient treated with preconditioning chemotherapy followed by CAR T cell infusion achieved MRD-negative status and subsequently underwent allo-HSCT.
- MSK-ALL06: A female patient relapsed after prior consolidation therapies; CAR T cells were administered, leading to MRD-negative status and successful allo-HSCT after infection resolution.

Persistence and Effectiveness Monitoring

The persistence of the 19-28z CAR-modified T cells was monitored through flow cytometry in both peripheral blood and bone marrow.
Responses to CD19 were assessed through serial samples, tracking the presence of malignant cell populations versus normal B cells using deep sequencing techniques.
Data showed a significant reduction in malignant IgH rearrangements post-treatment indicative of treatment efficacy.

Conclusion

The 19-28z CAR-modified T cell therapy shows promise as a viable treatment option for relapsed/refractory B-ALL, effectively bridging patients to potentially curative allo-HSCT with profound molecular remissions.

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Description

Explore the results of a study involving 5 patients treated with autologous T cells expressing a CD19-specific CAR for relapsed B-ALL. This quiz covers the effects of the therapy on persistent morphological disease and minimal residual disease (MRD), highlighting the rapid tumor eradication and remission achieved.