Tumor-infiltrating lymphocytes (TIL)**It has a history of more than 30 years and was first used forMalignant melanoma, and in recent years in moreSolid tumors** shows great potential.
At home and abroadtils**R&D are in full swing, including:Innovative **LN-144 (Lifileucel), TIL's new **KSQ-001EX, GT101 injection, etc.
Promotional image of the EMSO-IO conference.
Recently, in2023 emso-ioAt the opening ceremony of the (ESMO Immuno-Oncology) Congress, he was the father of immunology who created TIL**steven a.Professor RosenbergHe was awarded the 2023 ESMO Immuno-Oncology Award in recognition of himPioneering work on the first effective immunization**
At the conference, information on the ...til**Long-term benefitsand other new data, which have strengthened the potential of TIL in advanced melanoma, have emerged"Organoid" culture methodand other latest research. Next, let's take a look!
Til** has shown long-term efficacy in melanoma, with a 4-year survival rate of 219%
Study One:119o - long-term efficacy and patterns of response of lifileucel tumor-infiltrating lymphocyte (til) cell therapy in patients with advanced melanoma: a 4-year analysis of the c-144-01 study
Background: Patients with advanced (unresectable or metastatic) melanoma who are resistant to immune checkpoint inhibitors (ICIs) are large and in great demand. Lifileucel is a disposable autologous TIL cell**, which has demonstrated a long-lasting clinical benefit in this setting, with the C-144-01 study showing an ORR (objective response rate) of 31 in a heavily pretreated population4%。This article reports on C-144-01's lifileucel** results and reaction patternsData at 4-year follow-up
Methods: Data from patients in groups 2 and 4 were reported. Patient had 1 lesion excised (diameter 1.).5 cm), cryopreservation for 22 days. **ScenarioThese include nonmyeloablative lymphocyte clearance (cyclophosphamide 60 mg kg d 2 d, fludarabine 25 mg m2 d d 5 d), subsequentlySingle infusion of lifileuceland no more than 6 doses of high-dose IL-2 (600,000 IU kg).
Results: As of June 30, 2023, evaluated:153 patients, with a median follow-up of48.1 month。The Independent Review Committee is based on RECIST v11 assessed an ORR of 314%, and the median DOR (time to continuous remission) was NR (not reached). 1 year, 2 years, 3 yearsand 4-year OS (overall survival).The rates are. 4% and 219%。The median age of respondents (n=48) was 550 years old, the median of the previous ** route was 3.
Reaction patterns of OS and DOR.
It is important to note that clinically significant was observed in all modes of response4-year OS rate (range of 37.)2%–68.2%）；Patients with a deepened response had a numerically higher OS rate. **Current adverse events are consistent with the known safety profile of lymphodepletion and IL-2.
Conclusion:In this itemDuration of 4 yearsIn the analysis of advanced melanoma pretreatment, lifileucel** was generatedLong-lasting efficacy, brought in responders of different modesLong-term survival benefits
Data of 16 patients: TIL** combined with oncolytic adenovirus** is safe and feasible
Study 2:48o - safety and efficacy of combined treatment with tumor infiltrating lymphocytes (tils) and oncolytic adenovirus tilt-123 for patients with metastatic melanoma - results from a phase i trial
Background: Til** has recently been shown to be rightMetastatic melanomaPatients are effective. Oncolytic adenovirus TILT-123Equipped with tumor necrosis factor- and interleukin-2, they have been specifically selected to be able to:Enhances TIL cytotoxicitywithout pretreatment chemotherapy or post-treatment IL2.
Method: In onePhase I, open-label, 3+3 dose-escalation central trialPatients with stage IV melanoma received multiple intravenous and intratumoral injections of TILT-123 and one or two TIL**. tils is fromExcised tumor tissueand administered in the absence of pretreatment or post-pretreatment regimens. The primary endpoint of the study is the safety of TILT-123, and secondary endpoints include the safety and efficacy of TILT-123 in combination with TIL.
Results: Sixteen patients with progressive CPI (immune checkpoint inhibitor) resistance (7), mucosal (5), and uveal (4) metastatic melanoma were enrolled. The median age was 655 years old (25-75 years old). The most commonly reported adverse events (AEs) associated with TILT-123 were fever (63%) and pain (44%) at the injection site, while the most common adverse events associated with TIL** were fever (50%) and chills (24%). No dose-limiting toxicities were observed, andThe combined use of TILT-123 and TIL** does not increase the severity of AE。Of these, 31% experienced serious adverse events related to **.
Efficacy analysis of visugromab in combination with nivolumab** urothelial carcinoma.
On imaging on day 78, RECIST1 was observed in 2 patients1 reaction, whileThe disease control rate was 38% (6 16).。Responders included oneSustained partial reliefof patients (** and oneSustained complete remissionof patients (mucosa). In addition, two patients (uveal and **) had long-term stable disease (> 10 months). At the same time, the PET assessment at day 78 showed that 6 out of 13 patients could assess disease control, including:4 patients had partial or mild reactions。In addition, on day 36, after 4 injections of TILT-123 and before TIL, 4 partial or mild reactions were observed in PET assessments.
Conclusion:The combination of TILT-123 and TIL** is in patients with metastatic melanomaSafe and feasibleand observed clinical activity of the difficult-to-** subtype of melanoma.
Organoid culture before TIL expansion can improve the number of cells and anti-tumor activity
OrganoidsThe emergence of tumor immunity is providedNew opportunities。What are "organoids"?In fact, it is the tumor that is carried outVital excisionAfter special treatment, the in vitro three-dimensional model formed under specific culture conditions, it can be used to a large extentRetains the properties of the original tumor, thus creating a microenvironment that is infinitely close to the inside of human organs.
However, in the existing organoidsLack of immune cellsrestricts its development, so how should we seize this opportunity?
Organoid culture.
Study Three:151p - tumor organoid-derived til therapy for colorectal cancer
Background: Colorectal cancer (CRC) accounts for 7% of new cancer cases and 11% of cancer deaths worldwide. TIL immunization** is effective against melanoma, but itsEfficacy against epithelial cancers such as CRC remains inconsistent。The investigators hypothesize,Before TIL amplification, inTumor organoids grown in a gas-liquid interface (ALI) systemRare tumor-specific T cells that mediate antitumor activity may be selected.
Methods: Ali CRC organoids were created by as:Intact tumor fragmentsProduced by embedding in a collagen matrix on top of a permeable support membrane exposed to air and medium. This configuration contributes to optimal oxygenation, supporting the growth of faithful mini-replicas of the original tissue, which are replicatedStromal and tumor-infiltrated immune cells are preserved, including cytotoxic T cells.
To characterize the expanded ali tils in vitro, cell surface markers were analyzed by flow cytometry, single-cell RNA sequencing analysisImmune gene expression。The investigators also established in vitroSubmerged organoidsand take it asOrganoid-derived xenografts (ODX).Transplanted into mice to assess their antitumor activity. After induction by cytokines and in vitro co-cultureTumor cell deathto measure tumor reactivity and T cell toxicity while passingTumor growth inhibitionto evaluate preclinical in vivo efficacy.
Result: This ali process was producedHigh cell count, which is mainly composed of CD4+ and CD8+ T cells of effector and central memory subtypes. T cell receptor analysis reveals a unique set of polyclonal libraries suggestive of tumor specificity. Functionally, ali til tumor reactivity and killing were confirmed in vitro, which translates to:Potent in vivo antitumor activity against autologous ODX models
Conclusion:The study proposes aAn innovative TIL immuno** approach to colorectal cancer。Ali organoid culture conditions were applied prior to ex vivo TIL amplification, and generatedYesCell products with appropriate phenotypic and functional characteristics, which guarantees the further development of new processes.
Summary
As can be seen from numerous research data,The safety and efficacy of til**Constantly being verified, at the same time, based on:TIL identifies and infiltrates the intrinsic properties of solid tumors and their antitumor efficacyIt is expected to change the pattern of epithelial tumors such as lung cancer, gastric cancer, intestinal cancer, and breast cancer.
Of course, there are many challenges in applying TIL to the clinic**, even if TIL is obtained from tumor tissue, which canThe proportion of T cells that specifically recognize tumors is still low, which also limits the response rate and effectiveness of til**. However, new ways have been being explored, and we also look forward to the early approval of this new type of immunity, bringing new options to cancer patients
References: 1] Medina T, et al long-term efficacy and patterns of response of lifileucel tumor-infiltrating lymphocyte (til) cell therapy in patients with advanced melanoma: a 4-year analysis of the c-144-01 study. esmo immuno-oncology congress 2023, abstract 119o
2]monberg tj, et al. safety and efficacy of combined treatment with tumor infiltrating lymphocytes (tils) and oncolytic adenovirus tilt-123 for patients with metastatic melanoma: results from a phase i trial. esmo immuno-oncology congress 2023, abstract 48o
3]esmo immuno-oncology congress 2023 | oncologypro
Disclaimer: This article is only for health science popularization and cannot replace the examination and ** of the hospital. If you have any related diseases, please go to a regular medical institution for treatment in time and follow the doctor's instructions.