Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of Costimulated autologous T cells
Aaron P Rapoport, Edward A Stadtmauer, Nicole Aqui, Dan Vogl, Anne Chew, Hong-Bin Fang, Stephen Janofsky, Kelly Yager, Elizabeth Veloso, Zhaohui Zheng, Todd Milliron, Sandra Westphal, Julio Cotte, Hong Huynh, Andrea Cannon, Saul Yanovich, Gorgun Akpek, Ming Tan, Kristen Virts, Kathleen Ruehle, Carolynn Harris, Sunita Philip, Robert H Vonderheide, Bruce L Levine, Carl H June, Aaron P Rapoport, Edward A Stadtmauer, Nicole Aqui, Dan Vogl, Anne Chew, Hong-Bin Fang, Stephen Janofsky, Kelly Yager, Elizabeth Veloso, Zhaohui Zheng, Todd Milliron, Sandra Westphal, Julio Cotte, Hong Huynh, Andrea Cannon, Saul Yanovich, Gorgun Akpek, Ming Tan, Kristen Virts, Kathleen Ruehle, Carolynn Harris, Sunita Philip, Robert H Vonderheide, Bruce L Levine, Carl H June
Abstract
Purpose: Previously, we showed that adoptive transfer of in vivo vaccine-primed and ex vivo (anti-CD3/anti-CD28) costimulated autologous T cells (ex-T) at day +12 after transplant increased CD4 and CD8 T-cell counts at day +42 and augmented vaccine-specific immune responses in patients with myeloma. Here, we investigated the safety and kinetics of T-cell recovery after infusing ex-T at day +2 after transplant.
Experimental design: In this phase I/II two-arm clinical trial, 50 patients with myeloma received autografts after high-dose melphalan followed by infusions of ex-T at day +2 after transplant. Patients also received pretransplant and posttransplant immunizations using a pneumococcal conjugate vaccine only (arm B; n = 24) or the pneumococcal conjugate vaccine plus an HLA-A2-restricted microltipeptide vaccine for HLA-A2(+) patients (arm A; n = 26).
Results: The mean number of T cells infused was 4.26 x 10(10) (range, 1.59-5.0). At day 14 after transplant, the median CD3, CD4, and CD8 counts were 4,198, 1,545, and 2,858 cells/microL, respectively. Interleukin (IL)-6 and IL-15 levels increased early after transplant and IL-15 levels correlated significantly to day 14 T-cell counts. Robust vaccine-specific B- and T-cell responses were generated. T-cell infusions were well tolerated with no effect on hematopoietic recovery. Eight patients (16%) developed a T-cell "engraftment syndrome" characterized by diarrhea and fever that was clinically and histopathologically indistinguishable from grade 1 to 3 acute graft-versus-host disease (GVHD) of the gastrointestinal tract (seven patients) and/or grade 1 to 2 cutaneous GVHD (four patients).
Conclusions: Adoptive T-cell transfers achieve robust T-cell recovery early after transplant and induce moderate-to-severe autologous GVHD in a subset of patients.
Conflict of interest statement
Conflict of Interest Statement: A.P. Rapoport (corresponding author) has no conflicts of interest to declare. E.A. Stadtmauer has no conflicts of interest to declare. N.Aqui has no conflicts of interest to declare. D. Vogl has no conflicts of interest to declare. A. Chew has no conflicts of interest to declare. H-B. Fang has no conflicts of interest to declare. S. Janofsky has no conflicts of interest to declare. K. Yager has no conflicts of interest to declare. E. Veloso has no conflicts of interest to declare. Z. Zheng has no conflicts of interest to declare. T. Milliron has no conflicts of interest to declare. S. Westphal has no conflicts of interest to declare. J. Cotte has no conflicts of interest to declare. H. Huynh has no conflicts of interest to declare. A. Cannon has no conflicts of interest to declare. S. Yanovich has no conflicts of interest to declare. G. Akpek has no conflicts of interest to declare. M. Tan has no conflicts of interest to declare. K. Virts has no conflicts of interest to declare. K. Ruehle has no conflicts of interest to declare. C. Harris has no conflicts of interest to declare. R.H. Vonderheide declares a potential financial conflict of interest related to inventorship on a patent regarding hTERT as a tumor-associated antigen for cancer immunotherapy. B.L. Levine has no conflicts of interest to declare. C.H. June has no conflicts of interest to declare.
Figures
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Figure 3
A: CT scan of abdomen…
Figure 3
A: CT scan of abdomen showing thickened bowel wall (MD11). B: Crypt cell…
Figure 4
A: Grade III GVHD of…
Figure 4
A: Grade III GVHD of gut (MD30) showing apoptotic crypt cells (thin arrows)…
Figure 5
% Change in mean serum…
Figure 5
% Change in mean serum cytokine levels at various timepoints after stem cell…
- Combination immunotherapy after ASCT for multiple myeloma using MAGE-A3/Poly-ICLC immunizations followed by adoptive transfer of vaccine-primed and costimulated autologous T cells.Rapoport AP, Aqui NA, Stadtmauer EA, Vogl DT, Xu YY, Kalos M, Cai L, Fang HB, Weiss BM, Badros A, Yanovich S, Akpek G, Tsao P, Cross A, Mann D, Philip S, Kerr N, Brennan A, Zheng Z, Ruehle K, Milliron T, Strome SE, Salazar AM, Levine BL, June CH. Rapoport AP, et al. Clin Cancer Res. 2014 Mar 1;20(5):1355-65. doi: 10.1158/1078-0432.CCR-13-2817. Epub 2014 Feb 11. Clin Cancer Res. 2014. PMID: 24520093 Free PMC article. Clinical Trial.
- Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma.Rapoport AP, Aqui NA, Stadtmauer EA, Vogl DT, Fang HB, Cai L, Janofsky S, Chew A, Storek J, Akpek G, Badros A, Yanovich S, Tan MT, Veloso E, Pasetti MF, Cross A, Philip S, Murphy H, Bhagat R, Zheng Z, Milliron T, Cotte J, Cannon A, Levine BL, Vonderheide RH, June CH. Rapoport AP, et al. Blood. 2011 Jan 20;117(3):788-97. doi: 10.1182/blood-2010-08-299396. Epub 2010 Oct 28. Blood. 2011. PMID: 21030558 Free PMC article. Clinical Trial.
- Phase I trial of adoptive cell transfer with mixed-profile type-I/type-II allogeneic T cells for metastatic breast cancer.Hardy NM, Mossoba ME, Steinberg SM, Fellowes V, Yan XY, Hakim FT, Babb RR, Avila D, Gea-Banacloche J, Sportès C, Levine BL, June CH, Khuu HM, Carpenter AE, Krumlauf MC, Dwyer AJ, Gress RE, Fowler DH, Bishop MR. Hardy NM, et al. Clin Cancer Res. 2011 Nov 1;17(21):6878-87. doi: 10.1158/1078-0432.CCR-11-1579. Epub 2011 Sep 26. Clin Cancer Res. 2011. PMID: 21948234 Free PMC article. Clinical Trial.
- Alloreactivity as therapeutic principle in the treatment of hematologic malignancies. Studies of clinical and immunologic aspects of allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning.Petersen SL. Petersen SL. Dan Med Bull. 2007 May;54(2):112-39. Dan Med Bull. 2007. PMID: 17521527 Review.
- Cellular immunotherapy for plasma cell myeloma.Garfall AL, Vogl DT, Weiss BM, Stadtmauer EA. Garfall AL, et al. Bone Marrow Transplant. 2013 Nov;48(11):1377-86. doi: 10.1038/bmt.2013.54. Epub 2013 May 6. Bone Marrow Transplant. 2013. PMID: 23645169 Review.
- Glioblastoma, an opportunity T cell trafficking could bring for the treatment.Karimi-Shahri M, Khorramdel M, Zarei S, Attarian F, Hashemian P, Javid H. Karimi-Shahri M, et al. Mol Biol Rep. 2022 Oct;49(10):9863-9875. doi: 10.1007/s11033-022-07510-1. Epub 2022 May 23. Mol Biol Rep. 2022. PMID: 35604627 Review.
- Inhibition of glycolysis in the presence of antigen generates suppressive antigen-specific responses and restrains rheumatoid arthritis in mice.Mangal JL, Inamdar S, Le T, Shi X, Curtis M, Gu H, Acharya AP. Mangal JL, et al. Biomaterials. 2021 Oct;277:121079. doi: 10.1016/j.biomaterials.2021.121079. Epub 2021 Aug 20. Biomaterials. 2021. PMID: 34454372 Free PMC article.
- Ex Vivo High Salt Activated Tumor-Primed CD4+T Lymphocytes Exert a Potent Anti-Cancer Response.Tiriveedhi V, Ivy MT, Myles EL, Zent R, Rathmell JC, Titze J. Tiriveedhi V, et al. Cancers (Basel). 2021 Apr 2;13(7):1690. doi: 10.3390/cancers13071690. Cancers (Basel). 2021. PMID: 33918403 Free PMC article.
- 'Off-the-shelf' allogeneic CAR T cells: development and challenges.Depil S, Duchateau P, Grupp SA, Mufti G, Poirot L. Depil S, et al. Nat Rev Drug Discov. 2020 Mar;19(3):185-199. doi: 10.1038/s41573-019-0051-2. Epub 2020 Jan 3. Nat Rev Drug Discov. 2020. PMID: 31900462 Review.
- T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma.Garfall AL, Dancy EK, Cohen AD, Hwang WT, Fraietta JA, Davis MM, Levine BL, Siegel DL, Stadtmauer EA, Vogl DT, Waxman A, Rapoport AP, Milone MC, June CH, Melenhorst JJ. Garfall AL, et al. Blood Adv. 2019 Oct 8;3(19):2812-2815. doi: 10.1182/bloodadvances.2019000600. Blood Adv. 2019. PMID: 31575532 Free PMC article.
- Clinical Trial, Phase I
- Clinical Trial, Phase II
- Multicenter Study
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Adult
- Aged
- Algorithms
- Cells, Cultured
- Female
- Graft vs Host Disease / immunology
- Graft vs Host Disease / rehabilitation*
- HLA-A2 Antigen / metabolism
- Humans
- Immunotherapy, Adoptive* / adverse effects
- Immunotherapy, Adoptive* / methods
- Lymphocyte Activation / immunology
- Lymphocyte Activation / physiology
- Male
- Melphalan / therapeutic use
- Middle Aged
- Multiple Myeloma / immunology
- Multiple Myeloma / therapy*
- Myeloablative Agonists / therapeutic use
- Recovery of Function / immunology*
- Syndrome
- T-Lymphocytes / transplantation*
- Transplantation, Autologous
- HLA-A2 Antigen
- Myeloablative Agonists
- Melphalan
- Full Text Sources
- Medical
- Research Materials
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![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2828291/bin/nihms177281f5.jpg)
Source: PubMed