Adoptive T-cell Therapy: A Need for Standard Immune Monitoring

Klaver, Yarne; Kunert, Andre; Sleijfer, Stefan; Debets, Reno; Lamers, Cor H.J.

doi:10.2217/imt.15.23

Cited by 16 publications

(15 citation statements)

References 116 publications

(165 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, a correlation exists between characteristics of both baseline PBMC (proportion CD8 + T N ) and infusion product (proportion CD8 + T CE ) and numbers of circulation CAR T cells after treatment. Such findings bear clinical relevance, as younger T cells were shown to positively correlate with clinical effectiveness in adoptive T cell trials (1, 23, 24). To the best of our knowledge, our study is the first CAR T cell trial targeting a solid tumor, in which a correlation is demonstrated between pre-infusion and pre-expansion T cell characteristics and in vivo CAR T cell expansion potential.…”

Section: Discussionmentioning

confidence: 81%

“…Despite clinical successes in B-cell malignancies, adoptive transfer of T cells genetically modified with chimeric antigen receptors (CARs) or T cell receptors (TCRs) to treat solid tumors is challenged by limited patient responses (1). The efficacy of adoptive T cell therapy (in hematological malignancies) correlates with numbers and persistence of circulating modified T cells (2–5).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

T Cell Maturation Stage Prior to and During GMP Processing Informs on CAR T Cell Expansion in Patients

et al. 2016

Self Cite

View full text Add to dashboard Cite

Autologous T cells were genetically modified to express a chimeric antigen receptor (CAR) directed toward carboxy-anhydrase-IX (CAIX) and used to treat patients with CAIX-positive metastatic renal cell carcinoma. In this study, we questioned whether the T cell maturation stage in the pre-infusion product affected CAIX CAR expression and function in vitro as well as in vivo CAR T cell numbers and expansion. During the 14 days expansion of CAR T cells prior to administration, we observed shifts from a predominant CD4 to a CD8 T cell phenotype and from a significant fraction of naïve to central effector T cells. Surface expression of the CAR was equally distributed among different T cell subsets and T cell maturation stages. During T cell culture days 14–18 (which covered patient treatment days 1–5), T cells demonstrated a decline in CAR expression level per cell irrespective of T cell maturation stage, although the proportion of CAR-positive T cells and CAR-mediated T cell effector functions remained similar for both CD4 and CD8 T cell populations. Notably, patients with a higher fraction of naïve CD8 T cells at baseline (prior to genetic modification) or central effector CD8 T cells at 2 weeks of CAR T cell culture demonstrated a higher fold expansion and absolute numbers of circulating CAR T cells at 1 month after start of therapy. We conclude that the T cell maturation stage prior to and during CAR T cell expansion culture is related to in vivo CAR T cell expansion.

show abstract

Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

T Cell Maturation Stage Prior to and During GMP Processing Informs on CAR T Cell Expansion in Patients

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the vast majority of clinical studies, immunogenicity of the receptor has not been recognized as a possible limitation, most likely due to the applied non-myoablative preconditioning of patients in most studies, single T-cell infusions and a recent dominance of CD19 CAR T-cell studies [52,53]. Yet, our study clearly demonstrated the immunogenicity of xenogeneic protein sequences presented by T-cells [41].…”

Section: Recommendationsmentioning

confidence: 72%

“…To date, it has been shown that T-cell persistence and therapy efficiency improves from modification of the receptor design, in particular, by including a costimulatory domain in the receptor [52,53]. In addition, T-cells armoured with features that can adapt the immunesuppressive tumour microenvironment, e.g.…”

Section: Recommendationsmentioning

confidence: 99%

“…There still remains a need for markers in adoptive T-cell therapy, whether related to pre-treatment infusion product or post-treatment blood measurements, that correlate with therapy effectiveness [52]. Extensive monitoring of these experimental studies is a prerequisite for obtaining a better understanding of the biology and mechanisms and will reveal tools and recommendations to improve the adoptive receptorengineered T-cell approach.…”

Section: Recommendationsmentioning

confidence: 99%

See 1 more Smart Citation

Treatment of metastatic renal cell carcinoma (mRCC) with CAIX CAR-engineered T-cells–a completed study overview

Lamers

Klaver

Gratama

et al. 2016

Biochemical Society Transactions

Self Cite

126

View full text Add to dashboard Cite

We studied safety and proof of concept of a phase I/II trial with chimeric antigen receptor (CAR) T-cells in patients with metastatic renal cell carcinoma (mRCC). The CAR was based on the G250 mAb that recognized an epitope of carboxy-anhydrase-IX (CAIX). Twelve patients with CAIX+ mRCC were treated in three cohorts with a maximum of 10 daily infusions of 2×10(7) to 2×10(9) CAR T-cells. Circulating CAR T-cells were transiently detectable in all patients and maintained antigen-specific immune functions following their isolation post-treatment. Blood cytokine profiles mirrored CAR T-cell presence and in vivo activity. Unfortunately, patients developed anti-CAR T-cell antibodies and cellular immune responses. Moreover, CAR T-cell infusions induced liver enzyme disturbances reaching CTC grades 2-4, which necessitated cessation of treatment in four out of eight patients (cohort 1+2). Examination of liver biopsies revealed T-cell infiltration around bile ducts and CAIX expression on bile duct epithelium, adding to the notion of on-target toxicity. No such toxicities were observed in four patients that were pretreated with G250 mAb (cohort 3). The study was stopped due to the advent of competing treatments before reaching therapeutic or maximum tolerated dose in cohort 3. No clinical responses have been recorded. Despite that, from this trial numerous recommendations for future trials and their immune monitoring could be formulated, such as choice of the target antigen, format and immunogenicity of receptor and how the latter relates to peripheral T-cell persistence.

show abstract

Nuclear Imaging of CAR T Immunotherapy to Solid Tumors: In Terms of Biodistribution, Viability, and Cytotoxic Effect

et al. 2023

View full text Add to dashboard Cite

Immunotherapy has become a mainstay of cancer therapy. Since chimeric antigen receptor (CAR) T immunotherapy achieves unprecedented success in curing hematological malignancies, the possibility of it revolutionizing the paradigm of solid tumors has aroused increasing attention. However, the restricted accessibility to tumor parenchyma, the immunosuppressive tumor microenvironment, and antigen heterogeneity of solid tumors make it difficult to replicate its success. Therefore, dynamic evaluation of CAR T cells’ tumor accessibility, intratumoral viability, and anti‐tumor cytotoxicity is necessary to facilitate its translation to solid tumors. Besides, real‐timely imaging above events in vivo can help evaluate therapeutic responses and optimize CAR T immunotherapy for solid tumors. Nuclear imaging, including positron emission tomography (PET) and single‐photon emission computed tomography (SPECT) imaging, is frequently applied for evaluating adoptive cell therapies owing to its excellent sensitivity, high tissue penetration, and great translation potential. In addition, quantitative analysis can be performed in dynamic and noninvasive patterns. This review focuses on recent advances in PET/SPECT technologies and imaging probes in monitoring CAR T cells’ migration, viability, and cytotoxicity to solid tumors post‐administration. Prospects of what should be done in the next stage to promote CAR T therapy's application in solid tumors are also discussed.

show abstract

Adoptive T-cell Therapy: A Need for Standard Immune Monitoring

Cited by 16 publications

References 116 publications

T Cell Maturation Stage Prior to and During GMP Processing Informs on CAR T Cell Expansion in Patients

T Cell Maturation Stage Prior to and During GMP Processing Informs on CAR T Cell Expansion in Patients

Treatment of metastatic renal cell carcinoma (mRCC) with CAIX CAR-engineered T-cells–a completed study overview

Nuclear Imaging of CAR T Immunotherapy to Solid Tumors: In Terms of Biodistribution, Viability, and Cytotoxic Effect

Contact Info

Product

Resources

About