Neeta Pandit-Taskar1,2,3, Michael A Postow4,5, Matthew D Hellmann3,4,5, James J Harding4,5, Christopher A Barker6, Joseph A O'Donoghue7, Martha Ziolkowska8, Shutian Ruan8,2, Serge K Lyashchenko9,10, Frank Tsai11, Michael Farwell12, Tara C Mitchell12, Ron Korn13, William Le14, Jason S Lewis8,9,10, Wolfgang A Weber8, Deepak Behera14, Ian Wilson14, Michael Gordon11, Anna M Wu14,15, Jedd D Wolchok5. 1. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York pandit-n@mskcc.org. 2. Department of Radiology, Weill Cornell Medical College, New York, New York. 3. Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York. 4. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 5. Department of Medicine, Weill Cornell Medical College, New York, New York. 6. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. 7. Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York. 8. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. 9. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York. 10. Radiochemistry and Molecular Imaging Probes Core, Memorial Sloan Kettering Cancer Center, New York, New York. 11. Honor Health, Scottsdale, Arizona. 12. University of Pennsylvania, Philadelphia, Pennsylvania. 13. Imaging Endpoints, Scottsdale, Arizona. 14. ImaginAb, Inc., Inglewood, California; and. 15. Department of Molecular Imaging and Therapy, Beckman Research Institute of the City of Hope, Duarte, California.
Abstract
Immunotherapy is becoming the mainstay for treatment of a variety of malignancies, but only a subset of patients responds to treatment. Tumor-infiltrating CD8-positive (CD8+) T lymphocytes play a central role in antitumor immune responses. Noninvasive imaging of CD8+ T cells may provide new insights into the mechanisms of immunotherapy and potentially predict treatment response. We are studying the safety and utility of 89Zr-IAB22M2C, a radiolabeled minibody against CD8+ T cells, for targeted imaging of CD8+ T cells in patients with cancer. Methods: The initial dose escalation phase of this first-in-humans prospective study included 6 patients (melanoma, 1; lung, 4; hepatocellular carcinoma, 1). Patients received approximately 111 MBq (3 mCi) of 89Zr-IAB22M2C (at minibody mass doses of 0.2, 0.5, 1.0, 1.5, 5, or 10 mg) as a single dose, followed by PET/CT scans at approximately 1-2, 6-8, 24, 48, and 96-144 h after injection. Biodistribution in normal organs, lymph nodes, and lesions was evaluated. In addition, serum samples were obtained at approximately 5, 30, and 60 min and later at the times of imaging. Patients were monitored for safety during infusion and up to the last imaging time point. Results: 89Zr-IAB22M2C infusion was well tolerated, with no immediate or delayed side effects observed after injection. Serum clearance was typically biexponential and dependent on the mass of minibody administered. Areas under the serum time-activity curve, normalized to administered activity, ranged from 1.3 h/L for 0.2 mg to 8.9 h/L for 10 mg. Biodistribution was dependent on the minibody mass administered. The highest uptake was always in spleen, followed by bone marrow. Liver uptake was more pronounced with higher minibody masses. Kidney uptake was typically low. Prominent uptake was seen in multiple normal lymph nodes as early as 2 h after injection, peaking by 24-48 h after injection. Uptake in tumor lesions was seen on imaging as early as 2 h after injection, with most 89Zr-IAB22M2C-positive lesions detectable by 24 h. Lesions were visualized early in patients receiving treatment, with SUV ranging from 5.85 to 22.8 in 6 target lesions. Conclusion: 89Zr-IAB22M2C imaging is safe and has favorable kinetics for early imaging. Biodistribution suggests successful targeting of CD8+ T-cell-rich tissues. The observed targeting of tumor lesions suggests this may be informative for CD8+ T-cell accumulation within tumors. Further evaluation is under way.
Immunotherapy is becoming the mainstay for treatment of a variety of malignancies, but only a subset of patients responds to treatment. Tumor-infiltrating CD8-positive (CD8+) T lymphocytes play a central role in antitumor immune responses. Noninvasive imaging of CD8+ T cells may provide new insights into the mechanisms of immunotherapy and potentially predict treatment response. We are studying the safety and utility of 89Zr-IAB22M2C, a radiolabeled minibody against CD8+ T cells, for targeted imaging of CD8+ T cells in patients with cancer. Methods: The initial dose escalation phase of this first-in-humans prospective study included 6 patients (melanoma, 1; lung, 4; hepatocellular carcinoma, 1). Patients received approximately 111 MBq (3 mCi) of 89Zr-IAB22M2C (at minibody mass doses of 0.2, 0.5, 1.0, 1.5, 5, or 10 mg) as a single dose, followed by PET/CT scans at approximately 1-2, 6-8, 24, 48, and 96-144 h after injection. Biodistribution in normal organs, lymph nodes, and lesions was evaluated. In addition, serum samples were obtained at approximately 5, 30, and 60 min and later at the times of imaging. Patients were monitored for safety during infusion and up to the last imaging time point. Results:89Zr-IAB22M2C infusion was well tolerated, with no immediate or delayed side effects observed after injection. Serum clearance was typically biexponential and dependent on the mass of minibody administered. Areas under the serum time-activity curve, normalized to administered activity, ranged from 1.3 h/L for 0.2 mg to 8.9 h/L for 10 mg. Biodistribution was dependent on the minibody mass administered. The highest uptake was always in spleen, followed by bone marrow. Liver uptake was more pronounced with higher minibody masses. Kidney uptake was typically low. Prominent uptake was seen in multiple normal lymph nodes as early as 2 h after injection, peaking by 24-48 h after injection. Uptake in tumor lesions was seen on imaging as early as 2 h after injection, with most 89Zr-IAB22M2C-positive lesions detectable by 24 h. Lesions were visualized early in patients receiving treatment, with SUV ranging from 5.85 to 22.8 in 6 target lesions. Conclusion:89Zr-IAB22M2C imaging is safe and has favorable kinetics for early imaging. Biodistribution suggests successful targeting of CD8+ T-cell-rich tissues. The observed targeting of tumor lesions suggests this may be informative for CD8+ T-cell accumulation within tumors. Further evaluation is under way.
Authors: Herman Gill; Richard Seipert; Vincent M Carroll; Alexandra Gouasmat; Jian Yin; Annie Ogasawara; Isabella de Jong; Minh Michael Phan; Xiangdan Wang; Jihong Yang; Ohad Ilovich; Jan Marik; Simon-Peter Williams Journal: AAPS J Date: 2020-01-03 Impact factor: 4.009
Authors: Nils H Nicolay; Alexander Rühle; Nicole Wiedenmann; Gabriele Niedermann; Michael Mix; Wolfgang A Weber; Dimos Baltas; Martin Werner; Gian Kayser; Anca-L Grosu Journal: J Nucl Med Date: 2020-08-28 Impact factor: 10.057
Authors: Jordan M White; Outi M Keinänen; Brendon E Cook; Brian M Zeglis; Heather M Gibson; Nerissa T Viola Journal: Mol Pharm Date: 2020-05-12 Impact factor: 4.939
Authors: Pavlina Chuntova; Frances Chow; Payal B Watchmaker; Mildred Galvez; Amy B Heimberger; Evan W Newell; Aaron Diaz; Ronald A DePinho; Ming O Li; E John Wherry; Duane Mitchell; Masaki Terabe; Derek A Wainwright; Jay A Berzofsky; Christel Herold-Mende; James R Heath; Michael Lim; Kim A Margolin; E Antonio Chiocca; Noriyuki Kasahara; Benjamin M Ellingson; Christine E Brown; Yvonne Chen; Peter E Fecci; David A Reardon; Gavin P Dunn; Linda M Liau; Joseph F Costello; Wolfgang Wick; Timothy Cloughesy; William C Timmer; Patrick Y Wen; Robert M Prins; Michael Platten; Hideho Okada Journal: Neuro Oncol Date: 2021-03-25 Impact factor: 12.300