SSTR2 as an anatomical imaging marker and a safety switch to monitor and manage CAR T cell toxicity

Alcaina, Yago; Yang, Yanping; Vedvyas, Yogindra; McCloskey, Jaclyn E.; Jin, Moonsoo M.

doi:10.1038/s41598-022-25224-z

Cited by 5 publications

(6 citation statements)

References 52 publications

(72 reference statements)

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Section: Current Advances In Immuno-pet/-spect Imaging Methods and Th...mentioning

confidence: 99%

“…Notably, a recent study has gone one step further to investigate the potential of using the SSTR2 reporter as a suicide switch to destroy the CAR T-cells when they generate toxic AEs. In this approach, a maytansineoctreotate conjugate, PEN-221 (Tarveda), was used for imaging and elimination of CAR T-cells when they became toxic (200). Another interesting study used an engineered antibody against DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; DAbR1) for both cell tracking and a potential antibody-drug conjugate While most of these reporter/radiotracer studies are still at the preclinical stages, a successful first-in-human trial tracking CAR T-cells has been reported in the case of a 57-year-old man with grade IV glioblastoma whose autologous CD8 + T-cells were genetically engineered to express the herpes simplex virus type 1 thymidine kinase (HSV1-tk) suicide gene for PET imaging with 9-[4-[ 18 F]fluoro-3-(hydroxymethyl)butyl]guanine ([ 18 F]F-FHBG) (203).…”

Section: Car T-cell Distributionmentioning

confidence: 99%

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Current and potential roles of immuno-PET/-SPECT in CAR T-cell therapy

et al. 2023

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Chimeric antigen receptor (CAR) T-cell therapies have evolved as breakthrough treatment options for the management of hematological malignancies and are also being developed as therapeutics for solid tumors. However, despite the impressive patient responses from CD19-directed CAR T-cell therapies, ~ 40%−60% of these patients' cancers eventually relapse, with variable prognosis. Such relapses may occur due to a combination of molecular resistance mechanisms, including antigen loss or mutations, T-cell exhaustion, and progression of the immunosuppressive tumor microenvironment. This class of therapeutics is also associated with certain unique toxicities, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and other “on-target, off-tumor” toxicities, as well as anaphylactic effects. Furthermore, manufacturing limitations and challenges associated with solid tumor infiltration have delayed extensive applications. The molecular imaging modalities of immunological positron emission tomography and single-photon emission computed tomography (immuno-PET/-SPECT) offer a target-specific and highly sensitive, quantitative, non-invasive platform for longitudinal detection of dynamic variations in target antigen expression in the body. Leveraging these imaging strategies as guidance tools for use with CAR T-cell therapies may enable the timely identification of resistance mechanisms and/or toxic events when they occur, permitting effective therapeutic interventions. In addition, the utilization of these approaches in tracking the CAR T-cell pharmacokinetics during product development and optimization may help to assess their efficacy and accordingly to predict treatment outcomes. In this review, we focus on current challenges and potential opportunities in the application of immuno-PET/-SPECT imaging strategies to address the challenges encountered with CAR T-cell therapies.

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Section: Current Advances In Immuno-pet/-spect Imaging Methods and Th...mentioning

confidence: 99%

Section: Car T-cell Distributionmentioning

confidence: 99%

Current and potential roles of immuno-PET/-SPECT in CAR T-cell therapy

et al. 2023

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“…Alternative approach is to use a safety switch to eliminate CAR‐T cells once GvHD symptoms develop. For this purpose, Alcaina et al 62 used the combination of the somatostatin receptor 2 (SSTR2), as a suicide gene, with a specific maytansine‐octreotate conjugate PEN‐221. The results of their research highlight the role of SSTR2 not only in the imaging of CAR‐T cells expansion, but also in their removal, making it a promising dual marker.…”

Section: The Potential Of Personalized Allo‐car‐tmentioning

confidence: 99%

“…An applicable modality is magnetic cell separation (MACS); however, Kath et al 60 Alternative approach is to use a safety switch to eliminate CAR-T cells once GvHD symptoms develop. For this purpose, Alcaina et al 62 used the combination of the somatostatin receptor 2 (SSTR2), as a suicide gene, with a specific maytansine-octreotate conjugate PEN-221.…”

Section: Major Challengesmentioning

confidence: 99%

Are we ready for personalizedCAR‐Ttherapy?

Strzelec

Helbig

2023

European J of Haematology

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The future of chimeric antigen receptor T (CAR‐T) therapy remains unclear. New studies are constantly being published confirming the efficacy and favorable safety profile of its innovative enhancements. Currently approved CAR‐T drugs are manufactured exclusively for a specific patient from the recipient's own cells. This does not close the door to further modifications with subsequent personalization and better adaptation to the individual needs. Bringing such a drug to market would involve raising the already high costs, so it is necessary to lower the existing ones. On the other hand, so‐called universal CAR‐T are also getting closer to the patient's bed, but its implementation may struggle with multiple challenges, including development of graft‐versus‐host disease (GvHD) and alloimmunity. However, that off‐the‐shelf therapy could prove useful as a quick solution for patients in very poor condition or excluded from current therapy due to manufacturing limitations. The introduction of currently tested solutions may undoubtedly change the current paradigm of treatment.

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“…In our previous work, we developed CAR T cells co-expressing SSTR2 to enable positron emission tomography (PET) imaging of CAR T cell distribution in the whole body using 68 Ga-DOTATATE or 18 F-NOTA-Octreotide ( 19 , 20 ). Additionally, we demonstrated the use of SSTR2 as a suicide switch to deliver SSTR2-specific drug conjugates and eliminate unwanted CAR T cells that were causing systemic toxicity ( 21 ). In contrast to killing unwanted CAR T cells, this study investigates the effect of low to intermediate doses of radiation delivered by 177 Lu-DOTATATE to CAR T cells that are largely exhausted and dysfunctional yet proliferating within tumors ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

Low-dose targeted radionuclide therapy synergizes with CAR T cells and enhances tumor response

Yang,

Vedvyas,

Alcaina

et al. 2024

Front. Immunol.

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Ionizing radiation has garnered considerable attention as a combination partner for immunotherapy due to its potential immunostimulatory effects. In contrast to the more commonly used external beam radiation, we explored the feasibility of combining chimeric antigen receptor (CAR) T cell therapy with targeted radionuclide therapy (TRT), which is achieved by delivering β-emitting 177Lu-DOTATATE to tumor via tumor-infiltrating CAR T cells that express somatostatin receptor 2 (SSTR2). We hypothesized that the delivery of radiation to tumors could synergize with CAR T therapy, resulting in enhanced antitumor immunity and tumor response. To determine the optimal dosage and timing of 177Lu-DOTATATE treatment, we measured CAR T cell infiltration and expansion in tumors longitudinally through positron emission tomography (PET) using a SSTR2-specific positron-emitting radiotracer,18F-NOTA-Octreotide. In animals receiving CAR T cells and a low–dose (2.5 Gy) of TRT following the administration of 177Lu-DOTATATE, we observed a rapid regression of large subcutaneous tumors, which coincided with a dramatic increase in serum proinflammatory cytokines. Tumor burden was also reduced when a higher radiation dose (6 Gy) was delivered to the tumor. However, this higher dose led to cell death in both the tumor and CAR T cells. Our study suggests that there may exist an optimum range of TRT dosage that can enhance T cell activity and sensitize tumor cells to T cell killing, which may result in more durable tumor control compared to a higher radiation dose.

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SSTR2 as an anatomical imaging marker and a safety switch to monitor and manage CAR T cell toxicity

Cited by 5 publications

References 52 publications

Current and potential roles of immuno-PET/-SPECT in CAR T-cell therapy

Current and potential roles of immuno-PET/-SPECT in CAR T-cell therapy

Are we ready for personalizedCAR‐Ttherapy?

Low-dose targeted radionuclide therapy synergizes with CAR T cells and enhances tumor response

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