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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Enhanced cryoimmunotherapy against urogenital cancers

Alternative title: Innovativ cryoimmunterapi mot urogenital kreft

Awarded: NOK 16.6 mill.

The project is developing dendritic cell-based cryo-immunotherapy (CryoIT). Cancer cells are altered from normal cells and differ from patient to patient. CryoIT initiates NEW immune responses against cancer cells in each patient, regardless of how different the cancer cells are. Dendritic cells (DCs) are white blood cells found in very low numbers in the blood. A high proportion of white blood cells are composed of monocytes that can be reprogrammed into monocyte-derived DCs (moDCs) in cell culture. The primary function of DCs is to survey the body, constantly searching for something "foreign" - such as viruses and bacteria. Cancer cells differ from normal cells due to changes that DCs and moDCs perceive as "foreign." In CryoIT, cryoprobes are placed in the patient's tumor. Computer-controlled freezing and thawing kill parts of the tumor, releasing molecules from the cancer cells into the microenvironment. Millions of cultured DCs are then injected into the killed tissue to detect cancer-specific "foreign" molecules. The injected DCs initiate a much stronger anti-cancer immune attack than what the immune system is normally capable of achieving. Phase 1 clinical trial of CryoIT for 18 patients with metastatic castration-resistant prostate cancer was published this year (2023). Castration-resistant means that standard hormone-suppressing treatment no longer works for the patients. Early-stage prostate cancer often has a good prognosis, but this does not apply to the patient group that we treated with CryoIT. It is therefore gratifying that the median survival time for our treated patients is longer than what the literature reports for similar patient groups, and advanced biomarker analyses also indicate treatment effects and activation of the immune system against cancer cells. The regional ethics committee has approved a follow-up examination of patients using advanced biomarkers such as T-cell receptor sequencing and circulating tumor cells and nucleic acid analyses. A key task for the next generation of CryoIT is the robust production of more potent immune cells. For this purpose, new, partially automated production equipment, Miltenyi CliniMACS Prodigy, has been established. Blood obtained from patients through leukapheresis forms the basis of the production of therapeutic moDCs. The Prodigy system selects the monocytes and differentiates them into therapeutic moDCs. Over the past year, quality tests have been conducted to document that the cells meet defined requirements before patient treatment. The group has further investigated whether low levels of "natural" DCs circulating in the blood can be an alternative to moDCs. The result, published in 2023, suggests that the next clinical trial must be based on moDCs, as both the yield and short lifespan of the "natural" DCs currently pose significant practical challenges. The focus is instead on more potent moDCs through the control of critical regulatory mechanisms. The group is working on screening and developing new substances that can influence signaling pathways. Two patent processes are underway under the auspices of Vestlandets Innovasjonsselskap (VIS). An important aspect is to combine CryoIT with a lower dose of the immune checkpoint inhibitor ipilimumab injected into the cancer tissue alongside moDCs. The project has preliminary results in this regard, and a European patent has been granted. One of the most promising observations in the patients treated with CryoIT so far is that a large proportion of the most numerous T-cell clonotypes in the patients’ blood in the weeks after CryoIT are new or significantly expanded compared to clonotype repertoires before treatment. A T-cell clonotype is a subgroup with one particular type of T-cell receptor directed against a specific antigen. There are millions of T-cell clonotypes in the blood at any given time; some are numerous, while others have only a few T-cell copies. The project is now collaborating with groups in Bergen and Berlin to better analyze the CryoIT-induced clonotypes. New methodology is available to isolate these from the blood and investigate whether the subtypes are T-reg, Th1, Th2, Th17 as such subtypes have very different effects on cancer tissue, ranging from protective to lethal effects. Models are being established to demonstrate whether the newly formed T-cell clonotypes have the ability to penetrate cancer tissue and kill cancer cells. This represents a new level of precision in biomarkers and documentation of treatment effectiveness. An important consolidation of the project in the past year is the logistics approved by the regional ethics committee to obtain patient biopsies from cancer tissue along with blood samples for use in modeling cancer tissue in culture. This work is linked to the EU ERC project in Hamburg, INJURMET, which investigates whether surgical procedures release tumor cells into the bloodstream and which properties are essential for circulating tumor cells.

Cryoimmunotherapy (CryoIT) is currently tested on patients with metastatic prostate cancer in a Phase I Clinical Trial (Clinical.trials.gov. NCT02423928). The very recent interim analysis of the 13 first treated patients motivates the present project application. Cancer cell heterogeneity is the main underlying reason that invasive cancer exhibits resistance and relapses following therapy. CryoIT is a unique concept because it can tackle the formidable challenge of cell heterogeneity. Dendritic cells (DCs) are the most efficient antigen-presenting cells of our body. According to CryoIT, large numbers of the patients’ own DCs are injected into the cancer tissue inside the body following cryoablation (freezing) by advanced equipment. DCs thereby can find and present to the immune system any tumor-associated antigen. Additionally, freezing creates inflammation that stimulates DCs and immune attack. The interim analysis concludes that CryoIT is safe and well tolerated and with several treatment effects as measured by radiology, circulating tumor cells and immunomonitoring. Most importantly, ultradeep DNA sequencing of the T-cell receptor revealed that NEW and robust T-lymphocyte clones formed following CryoIT. This is evidence of immune activation against the tumor. Phase I/IIA clinical trial is now planned as a BASKET trial, meaning that several different cancer types can be treated. Several possibilities to increase treatment efficiency will be approached in the present project: a) intervention at earlier stage disease; b) booster strategy with repeated DC vaccination which until now was done one time per patient; c) enhancement of the NEW immune clones by FDA-approved compounds that stimulate the immune attack and counteract immune evasion. Integrated tasks are therapeutic DC production in Bergen and establishment of model systems, including ex vivo DC and organoid cultures to test drug compounds and establish extended quality control of improved DC preparations.

Publications from Cristin

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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering