PET Imaging for Non-Hodgkin's Lymphoma

Overseen By UCSF Hematopoietic Malignancies Clinical Trial Recruitment

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: C. Babis Andreadis

Must be taking: CD19 CAR-T therapy

Disqualifiers: Pregnancy, Hypersensitivity, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

32 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. It's best to discuss your specific medications with the trial team to get a clear answer.

What data supports the effectiveness of the treatment 64Cu-GRIP B for Non-Hodgkin's Lymphoma?

Research shows that 64Cu-GRIP B can detect granzyme B activity, which is linked to immune cell activation, in cancer models. This suggests it might help monitor immune responses in Non-Hodgkin's Lymphoma, similar to its use in other cancers. ^{1 2 3 4 5}

Is 64Cu-GRIP B safe for use in humans?

The research on similar Copper-64 labeled compounds, like 64Cu-LLP2A and 64Cu-daratumumab, shows they were well-tolerated in human studies with no significant adverse events reported, suggesting a favorable safety profile for Copper-64 labeled agents in general. ^{6 7 8 9 10}

How does PET imaging differ from other treatments for Non-Hodgkin's Lymphoma?

PET imaging for Non-Hodgkin's Lymphoma is unique because it uses a special imaging technique to visualize the activity of granzyme B, a protein involved in immune responses, which can help assess the effectiveness of immunotherapy treatments. This approach allows for non-invasive monitoring of how well the immune system is targeting cancer cells, which is different from traditional treatments that focus on directly attacking the cancer cells themselves. ^{2 4 11 12 13}

What is the purpose of this trial?

This is a phase I/Ib imaging study of granzyme B, 64-copper granzyme targeting restricted interaction peptide specific to family member B (64Cu-GRIP B) Positron Emission Tomography (PET) in patients with relapsed/refractory non-Hodgkin's lymphoma (NHL) receiving CD19-directed Chimeric antigen receptor T cells (CAR-T) therapy. The proposed study represents the first-ever lymphoma patient imaging studies with 64Cu-GRIP B PET. The tracer is designed to detect extracellular granzyme B as it is secreted by activated immune cells in the tumor microenvironment, which may highlight tumors that will exhibit a durable response to Cluster of Differentiation 19 (CD19)-directed CAR T-cell therapy.

Research Team

C. Babis Andreadis, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for individuals with relapsed/refractory non-Hodgkin's lymphoma who are undergoing CD19-directed CAR-T therapy. Participants must meet certain health criteria to be eligible, but specific inclusion and exclusion details were not provided.

Inclusion Criteria

I agree to have biopsies after treatment and have a tumor that can be safely biopsied.

I can do most of my daily activities without help.

Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Any condition that would impair the participant's ability to comply with study procedures

Pregnant participants

I am allergic to 64Cu-GRIP B or its ingredients.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo 64Cu-GRIP B PET imaging before and after CD19-directed CAR-T therapy

4 weeks

Multiple visits for PET imaging and CAR-T therapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Regular follow-up visits

Treatment Details

Interventions

• 64Cu-GRIP B

Trial Overview The study tests a new PET imaging agent called 64Cu-GRIP B in patients receiving CAR-T therapy. It aims to see if this tracer can identify which tumors will respond well to the treatment by detecting a molecule released by immune cells.

Participant Groups

Group I: Cohort 2: Expansion Phase 64Cu-GRIP B PET imaging Experimental Treatment 3 Interventions

Participants with NHL will undergo 64Cu-GRIP B PET before and after CD19-directed CAR-T therapy with one of the three time points chosen based on 64Cu-GRIP B uptake determined in Cohort 1. An optional soft tissue biopsy will be collected following the post-treatment PET. Participants will be followed up for 12 months after the final PET scan.

Group II: Cohort 1: 64Cu-GRIP B PET imaging Experimental Treatment 3 Interventions

Participants with NHL will undergo 64Cu-GRIP B PET before and after CD19-directed CAR-T therapy. Three participants will undergo post-treatment 64Cu-GRIP B PET at the Day 8 time point, three participants will undergo post-treatment 64Cu-GRIP B PET at the Day 15 (+/- 3) time point, and three participants will undergo post-treatment 64Cu-GRIP B PET Day 22 (+/- 3) time point. An optional soft tissue biopsy will be collected following the post-treatment PET. Participants will be followed up for 12 months after the final PET scan.

Who Is Running the Clinical Trial?

C. Babis Andreadis

Lead Sponsor

Trials

5

Recruited

130+

The V Foundation

Collaborator

Trials

10

Recruited

320+

Findings from Research

Researchers developed new near-infrared fluorogenic substrates that can detect active granzyme A (GzmA) in both human and mouse models, providing a highly efficient and selective tool for studying immune responses against tumors.

These probes allow for real-time imaging of how cytotoxic immune cells, like T lymphocytes and natural killer cells, respond to cancer cells, enhancing our understanding of the immune response in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluorogenic Granzyme A Substrates Enable Real-Time Imaging of Adaptive Immune Cell Activity. Cheng, Z., Thompson, EJ., Mendive-Tapia, L., et al.[2023]

The study developed novel SPECT imaging probes, [111 In]IDT and [111 In]IDAT, which effectively target granzyme B, a promising biomarker for enhancing immune checkpoint inhibitor treatments.

In experiments with tumor-bearing mice, these probes demonstrated moderate accumulation in tumors, correlating with granzyme B expression, suggesting their potential utility in monitoring treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and evaluation of 111 In-labeled tetrapeptide-based compounds as single-photon emission computed tomography imaging probes targeting granzyme B. Kazuta, N., Watanabe, H., Ono, M.[2023]

The study demonstrated that the PET imaging agent [18F]AlF-mNOTA-GZP can effectively differentiate between cancer treatment responders and non-responders in a mouse model, indicating its potential as a biomarker for assessing the effectiveness of combined chemotherapy and immune checkpoint inhibitor therapies.

The uptake of [18F]AlF-mNOTA-GZP was positively correlated with the presence of Granzyme B-expressing immune cells, such as GZB+ CD8+ T cells and GZB+ NK+ cells, suggesting that Granzyme B plays a crucial role in the immune response to treatment and can serve as a reliable indicator of tumor response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Granzyme B PET Imaging of Combined Chemotherapy and Immune Checkpoint Inhibitor Therapy in Colon Cancer. Goggi, JL., Hartimath, SV., Xuan, TY., et al.[2022]

A new imaging technology, using a specially engineered peptide called GRIP B, allows researchers to measure the activity of granzyme B (GZMB) in living organisms, providing insights into its biological functions in real-time.

In mouse cancer models, this method successfully detected GZMB activity in tumors and lymphoid tissues, indicating its potential role in immune responses, especially when combined with immune checkpoint inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vivo Measurement of Granzyme Proteolysis from Activated Immune Cells with PET. Zhao, N., Bardine, C., Lourenço, AL., et al.[2023]

The PET imaging technique using the granzyme B-targeted radiotracer 68Ga-grazytracer can effectively predict tumor responses to immunotherapy, showing better sensitivity in distinguishing responders from nonresponders compared to traditional methods.

In a preliminary clinical trial with 5 patients, 68Ga-grazytracer was safe with no adverse events reported, and its PET results correlated well with clinical responses to immunotherapy, suggesting its potential for improving patient stratification and early response assessment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Noninvasive interrogation of CD8+ T cell effector function for monitoring early tumor responses to immunotherapy. Zhou, H., Wang, Y., Xu, H., et al.[2022]

The phase 1 trial demonstrated that 64Cu-daratumumab PET/CT is a safe imaging technique for detecting multiple myeloma, with no significant adverse events reported in 12 patients.

Using 45 mg of unlabeled daratumumab improved image quality by reducing background signal, suggesting that 64Cu-daratumumab may offer better sensitivity and specificity compared to traditional FDG PET/CT for identifying multiple myeloma lesions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identifying CD38+ cells in patients with multiple myeloma: first-in-human imaging using copper-64-labeled daratumumab. Krishnan, A., Adhikarla, V., Poku, EK., et al.[2022]

The VLA4-targeted radiopharmaceutical 64Cu-LLP2A demonstrated a favorable safety profile in both animal and human studies, with no adverse effects observed in human participants after administration.

In human trials, 64Cu-LLP2A showed effective biodistribution and rapid clearance from the bloodstream, making it a promising imaging agent for multiple myeloma, with optimal imaging occurring 4-5 hours post-injection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Humans Evaluation of Safety and Dosimetry of 64Cu-LLP2A for PET Imaging. Laforest, R., Ghai, A., Fraum, TJ., et al.[2023]

The study developed a method to reduce kidney radioactivity from Copper-64 (64Cu)-labeled antibody fragments by designing a compound that liberates a radiometabolite for urinary excretion, which is beneficial for molecular imaging and radioimmunotherapy.

When tested in mice, the new 64Cu-labeled antibody fragment showed similar tumor targeting but significantly lower kidney radioactivity compared to traditional methods, indicating improved safety without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Copper-64-Labeled Antibody Fragments for Immuno-PET/Radioimmunotherapy with Low Renal Radioactivity Levels and Amplified Tumor-Kidney Ratios. Suzuki, H., Kise, S., Kaizuka, Y., et al.[2021]

The chelator pycup and its derivatives provide strong stability for (64)Cu in PET imaging, showing very slow decomplexation even under harsh conditions, which is crucial for effective imaging.

In vivo studies demonstrated that pycup2A, when conjugated to a fibrin-targeted peptide, successfully enabled PET imaging of arterial thrombosis in a rat model, highlighting its potential for targeted diagnostic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pycup--a bifunctional, cage-like ligand for (64)Cu radiolabeling. Boros, E., Rybak-Akimova, E., Holland, JP., et al.[2021]

The study demonstrated that 64Cu-labeled ch14.18 antibodies can specifically target neuroblastoma tumors, achieving a high accumulation rate of 31.6% ID/g in preclinical models, indicating their potential efficacy for targeted therapy.

Clinical PET/MRI scans using the radiolabeled antibodies successfully visualized neuroblastoma metastases in a patient, suggesting that this theranostic approach could be a valuable tool for therapy planning in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Translational immunoPET imaging using a radiolabeled GD2-specific antibody in neuroblastoma. Schmitt, J., Schwenck, J., Maurer, A., et al.[2022]

In a study of 69 lymphoma cases in the upper aerodigestive tract, granzyme B was found to be a reliable marker for diagnosing T/NK-cell lymphomas, as all cases expressing CD56 and T-cell markers showed strong granzyme B immunoreactivity.

The monoclonal antibody to granzyme B (GrB-7) proved effective for diagnosis without needing special tissue processing techniques, making it a practical tool for identifying T/NK-cell lymphomas alongside CD56.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Granzyme B immunoreactivity in T/natural killer cell lymphomas. Cho, MS., Lee, MK., Yang, WI., et al.[2015]

Granzyme B PET imaging using the targeted peptide GZP is a highly sensitive and specific method for early assessment of response to cancer immunotherapy, showing 93% sensitivity and 94% negative predictive value in predicting treatment outcomes.

The study demonstrated that GZP PET imaging can effectively compare the efficacy of different checkpoint inhibitor regimens, revealing that sequential dosing of PD-1 and CTLA-4 therapies is as effective as concurrent administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effectiveness of Checkpoint Inhibitor Combinations and Administration Timing Can Be Measured by Granzyme B PET Imaging. Larimer, BM., Bloch, E., Nesti, S., et al.[2020]

A novel granzyme B-targeted PET imaging agent (GZP) was successfully used in a murine model to non-invasively identify immune-related adverse events (irAEs) associated with cancer immunotherapy, highlighting its potential for monitoring these events in patients.

The study found that GZP PET imaging showed increased uptake in organs affected by irAEs, such as the colon and spleen, which decreased after treatment with the immunosuppressor dexamethasone, indicating a direct correlation between granzyme B presence and the severity of irAEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-invasive Detection of Immunotherapy-Induced Adverse Events. Ferreira, CA., Heidari, P., Ataeinia, B., et al.[2022]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Fluorogenic Granzyme A Substrates Enable Real-Time Imaging of Adaptive Immune Cell Activity. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Synthesis and evaluation of 111 In-labeled tetrapeptide-based compounds as single-photon emission computed tomography imaging probes targeting granzyme B. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Granzyme B PET Imaging of Combined Chemotherapy and Immune Checkpoint Inhibitor Therapy in Colon Cancer. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

In Vivo Measurement of Granzyme Proteolysis from Activated Immune Cells with PET. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Noninvasive interrogation of CD8+ T cell effector function for monitoring early tumor responses to immunotherapy. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Identifying CD38+ cells in patients with multiple myeloma: first-in-human imaging using copper-64-labeled daratumumab. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

First-in-Humans Evaluation of Safety and Dosimetry of 64Cu-LLP2A for PET Imaging. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Copper-64-Labeled Antibody Fragments for Immuno-PET/Radioimmunotherapy with Low Renal Radioactivity Levels and Amplified Tumor-Kidney Ratios. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Pycup--a bifunctional, cage-like ligand for (64)Cu radiolabeling. [2021]

10. Australia pubmed.ncbi.nlm.nih.gov

Translational immunoPET imaging using a radiolabeled GD2-specific antibody in neuroblastoma. [2022]

11. Korea (South) pubmed.ncbi.nlm.nih.gov

Granzyme B immunoreactivity in T/natural killer cell lymphomas. [2015]

12. United States pubmed.ncbi.nlm.nih.gov

The Effectiveness of Checkpoint Inhibitor Combinations and Administration Timing Can Be Measured by Granzyme B PET Imaging. [2020]

13. United States pubmed.ncbi.nlm.nih.gov

Non-invasive Detection of Immunotherapy-Induced Adverse Events. [2022]