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3 minute read
Adoptive cell therapies (ACTs) are being broadly tested and implemented in the treatment of a wide range of cancers, but the success of these therapies has been limited by the challenges of expanding cells of interest ex vivo. Most studies collect peripheral blood cells from a patient and expand, enrich or modify tumor-specific cells in a laboratory environment to create a blood product with tumor-targeting cells that can be reinfused into the patient. If the blood product is re-infused into the same patient, it is considered an autologous transplant, but if the cells originate from a different donor, it is considered an allogeneic transplant.
Autologous and allogeneic culture systems are essential to creating ACTs but the conditions used for expansion do not always expand cell subsets of interest. Tumor-infiltrating lymphocytes (TILs) are of particular interest for ACT-based treatment of solid tumors, but these cells can be challenging to expand ex vivo. Autologous TILs are isolated from a patient’s tumor tissue and expanded ex vivo under specific conditions to support the expansion of tumor-specific cytotoxic T cells before reinfusion into a patient. Autologous TILs were first shown to be effective in treating advanced melanoma and have been used to treat other solid tumors[1],[2]. Autologous TILS have several therapeutic advantages as these cells are from the patient so do not cause transplant mismatch complications and contain T cells that specifically target the patient’s tumors. Autologous cell expansion is expensive as it must be done in a patient specific manner and these cells can only be passaged a limited number of times ex vivo before senescence is induced, which causes functional changes to expanded cells. Unfortunately, several studies have revealed that autologous TIL expansion can result in suboptimal ACT products, either due to loss of cytotoxic or functional characteristics of the tumor-targeting cells[3], or due to expansion T cell subsets that are not a best match for tumor targeting but outpace ex vivo expansion of T cell subsets of interest[4].
Allogeneic transplantation is an alternative to autologous transplantation and typically requires the expansion of hematopoietic stem cells (HSCs) derived from the bone marrow or cord blood. Allogeneic HSC transplantation has been an essential treatment for numerous hematological malignancies in which radiation or chemotherapy has been used to ablate all host HSCs, and this treatment has also been successful for some solid tumors like neuroblastoma[5]. Large batches of allogeneic HSCs can be expensive to expand and validate initially but can be passaged many times and cryopreserved thus reducing long-term costs. HSCs are less differentiated precursor cells so allogeneic transplantation can also avoid some of the complications associated with immune transplantation mismatch, but graft-versus-host-disease can be induced by mismatch responses which is a potential negative side effect associated with treatment failure.
CAR-T cell therapy is an area of great promise in cancer immunotherapy and is a type of ACT that can use either autologous or allogeneic T cells. These T cells are modified ex vivo to express chimeric antigen receptors (CAR) that target T cell receptor activation coupled with costimulatory signaling for redirected anti-tumor T cell responses[6]. Anti-CD19 CAR-T cell therapies showed impressive results for the treatment of B cell hematologic malignancies, and large scale manufacturing processes have made this a scalable treatment option. Further progress in CAR-T cell therapy has been limited by studies showing tumor relapse, poor cytotoxic responses, and limited access of CAR-T cells to the tumor microenvironment, thus leading to current studies with new CAR constructs or treatment combinations[7].
Current preclinical studies are seeking to understand how to culture cells ex vivo for improved, sustained anti-tumor responses with little or no off-target effects. Advances in both basic immunology and cell manufacturing processes are improving the efficacy of both autologous and allogeneic ACT products.
[1] Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011; 17(13):4550–4557.
[2] Andersen R, Donia M, Ellebaek E, Borch TH, Kongsted P, Iversen TZ, Hölmich LR, Hendel HW, Ö M, Andersen MH, et al. Long-lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumor-infiltrating lymphocytes and an attenuated IL2 regimen. Clin Cancer Res. 2016; 22(15):3734–3745.
[3] van Asten SD, de Groot R, van Loenen MM, et al. T cells expanded from renal cell carcinoma display tumor-specific CD137 expression but lack significant IFN-γ, TNF-α or IL-2 production. Oncoimmunology. 2021;10(1):1860482.
[4] Poschke IC, Hassel JC, Rodriguez-Ehrenfried A, Lindner KAM, Heras-Murillo I, Appel LM, Lehmann J, Lövgren T, Wickström SL, Lauenstein C, Roth J, König AK, Haanen JBAG, van den Berg J, Kiessling R, Bergmann F, Flossdorf M, Strobel O, Offringa R. The Outcome of Ex Vivo TIL Expansion Is Highly Influenced by Spatial Heterogeneity of the Tumor T-Cell Repertoire and Differences in Intrinsic In Vitro Growth Capacity between T-Cell Clones. Clin Cancer Res. 2020; 26(16):4289-4301.
[5] Maung, Ko K., and Mitchell E. Horwitz. "Current and future perspectives on allogeneic transplantation using ex vivo expansion or manipulation of umbilical cord blood cells." Int. J. Hemat. 2019. 110.1:50-58.
[6] Yang Y, Jacoby E, Fry TJ. Challenges and opportunities of allogeneic donor-derived CAR T cells. Curr Opin Hematol. 2015;22(6):509-515.
[7] Huang R, Li X, He Y, Zhu W, Gao L, Liu Y, Gao L, Wen Q, Zhong JF, Zhang C, Zhang X. Recent advances in CAR-T cell engineering. J. Hematol Oncol. 2020;13(1):86.
