Clinical Trial Details
— Status: Recruiting
Administrative data
NCT number |
NCT06108596 |
Other study ID # |
PRSYM202310 |
Secondary ID |
|
Status |
Recruiting |
Phase |
Phase 1/Phase 2
|
First received |
|
Last updated |
|
Start date |
December 21, 2023 |
Est. completion date |
December 31, 2024 |
Study information
Verified date |
June 2024 |
Source |
The First Affiliated Hospital with Nanjing Medical University |
Contact |
Yueming Sun, MD, PhD |
Phone |
02568306026 |
Email |
jssym[@]vip.sina.com |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
Evaluation of the efficacy and safety of interleucin-2 combined with PD-1 monoclonal antibody
and CAPOX in preoperative neoadjuvant therapy for locally advanced rectal cancer - a
single-center, single-arm, open-label clinical trail.
Description:
The global incidence rate of rectal cancer is approximately 732,000 cases/year, of which a
significant proportion is locally advanced rectal cancer (i.e., T3-4 or N+). Currently, for
locally advanced rectal cancer, the NCCN guidelines recommend treatment with neoadjuvant
radiotherapy and chemotherapy + total mesorectal excision + adjuvant chemotherapy, reducing
the local recurrence rate of locally advanced rectal cancer from over 30% to less than 10%.
However, this treatment mode still has a low overall sphincter preservation rate, a high
distant metastasis rate, and limited overall survival (OS) benefits. In recent years, the
emergence of total neoadjuvant therapy (TNT) strategies, including induction chemotherapy +
concurrent chemoradiotherapy + surgery, concurrent chemoradiotherapy + consolidation
chemotherapy (two or even three drugs) + surgery, and concurrent chemoradiotherapy +
consolidation immunotherapy combined with chemotherapy + surgery, have all improved the
long-term prognosis of locally advanced rectal cancer to varying degrees. However, the TNT
mode is not suitable for all rectal cancer patients. For patients with low or moderate-risk
rectal cancer or those who cannot tolerate intensive radiotherapy and chemotherapy, TNT
increases the potential risk of overtreatment and associated toxicity.
The emergence of immunotherapy, including adoptive cell transfer (ACT) and immune checkpoint
inhibitors (ICB), provides new insights into the treatment of locally advanced rectal cancer.
However, most colorectal cancer patients have a limited response to immunotherapy. For ACT,
many clinical studies report that exogenously infused antitumor T cells have poor tumor
tissue infiltration, resulting in extremely limited immune responses. This inefficiency in T
cell delivery may be due to high interstitial fluid pressure, pathological vascular networks,
tumor-associated fibroblasts, or the "physical barrier" of the extracellular matrix (ECM), as
well as the immunosuppressive tumor microenvironment. As for immune checkpoint inhibitors
(ICIs), especially PD-1/PD-L1 targeted therapies, they have shown significant promise in the
treatment of various solid tumors, including breast cancer, lung cancer, gastric cancer, and
colorectal cancer. Studies such as CheckMate-142 and KEYNOTE-177 have confirmed the excellent
efficacy of PD-1/PD-L1 inhibitors in the treatment of colorectal cancers with mismatch repair
protein defects (dMMR) or high microsatellite instability (MSI-H). Institutions like the
Memorial Sloan Kettering Cancer Center (MSKCC), Sun Yat-sen University Cancer Center, and the
Sixth Affiliated Hospital of Sun Yat-sen University have conducted research on PD-1
inhibitors for neoadjuvant treatment of locally advanced rectal cancer, with complete
remission rates as high as 75% to 100%. However, this patient population is very small,
accounting for about 15% of early-stage colorectal cancers and only 5% of advanced colorectal
cancers, especially less than 5% in rectal cancer. Meanwhile, microsatellite stable (MSS)
patients make up the vast majority of colorectal cancers, and they benefit little from
single-agent immunotherapy.
In this population, low tumor mutation burden (TMB) and insufficient immunogenicity, leading
to inadequate immune cell infiltration, are considered one of the main resistance mechanisms
to immunotherapy. Therefore, enhancing immune cell infiltration and boosting the therapeutic
effect of immunotherapy in low-responsive colorectal cancer has significant clinical
importance. Currently, some clinical experiments are being conducted in this area. For
instance, radiotherapy theoretically synergizes with immunotherapy, possibly through the
release of tumor antigens, remodeling of the immune microenvironment, and increasing
antitumor immune responses, thus producing a combined therapeutic effect. Prospective phase
II studies suggest that radiotherapy combined with immunotherapy achieves a higher pCR rate
in pMMR/MSS locally advanced rectal cancer. Additionally, various immune cells in the tumor
microenvironment (TME) can impair tumor immune responses, leading to tumor resistance to PD-1
therapy. Much evidence suggests that T cells in or near tumor tissues, although activated,
cannot attack tumor cells. Thus, enhancing T cell tumor infiltration and activating their
antitumor effects are key methods to enhance PD-1 therapy. Recent basic research results show
that elevated levels of TGF-β and VEGF in tumor tissues suppress the aforementioned
cytokines, enhancing tumor T cell infiltration and the efficacy of anti-PD-1 therapy.
Moreover, a phase Ib clinical trial from Australia suggests that Pixatimod (a TLR9 agonist)
combined with Nivolumab shows tolerability and clinical benefits in MSS mCRC patients, and
researchers also observed pharmacodynamic changes and biomarker signals related to clinical
benefits in the combination scheme. Similarly, another phase I clinical trial suggests that
low molecular weight heparin (LMWH) enhances the efficacy of anti-PD-1 in MSS colorectal
cancer by increasing CD8+T cell infiltration. These results highlight the immense prospects
of PD-1 therapy combined with immune enhancement in antitumor immunotherapy.
IL-2 (Interleukin-2) is an essential cytokine, primarily produced by activated T cells. It
plays a pivotal role in the immune system by promoting the growth and differentiation of T
cells, enhancing the activity of cytotoxic T cells (CTLs) and natural killer cells (NK
cells), and participating in immune responses against pathogens and tumors. In past tumor
treatments, the primary application of IL-2 was to initiate and amplify the body's immune
attack on tumors. In the treatment of certain diseases, such as malignant melanoma and renal
cancer, monotherapy with appropriate doses of IL-2 has proven beneficial. For instance, a low
dose of IL-2 20IU subcutaneous injection can induce immune activation while producing fewer
clinical side effects. However, the complications of high-dose IL-2 treatment can be severe,
including hypotension, respiratory distress, and renal impairment. Although IL-2 has some
application in tumor immunotherapy, its efficacy is often limited, benefiting only a minority
of patients. Current research is exploring ways to enhance the effectiveness of IL-2,
including the development of novel IL-2 variants that improve the molecule's selectivity and
stability, as well as combination therapies with other immune modulators, such as checkpoint
inhibitors. In certain conditions, such as Lymphocytic Choriomeningitis Virus (LCMV)
infection, the combined treatment of PD-1 and IL-2 has shown remarkable clinical efficacy. In
vivo experiments indicate that, compared to PD-1 monotherapy, the combination of PD-1+IL-2
for LCMV significantly alters the differentiation program of PD-1+TCF1+ stem-like CD8+T
cells, producing effector CD8+T cells distinct at the transcriptional and epigenetic levels,
very similar to those observed after acute viral infections. Furthermore, in head and neck
squamous cell carcinoma (HNSCC), a bispecific immune cytokine PD1-IL2v can notably activate
immune cells, including NK cells and CD8+T cells, and inhibit the proliferation and
metastasis of tumor cells. These discovered mechanisms elucidate the potential synergy
between IL-2 treatment and PD-1 blockade, providing guidance and a theoretical foundation for
our clinical trial using the combination of PD-1 and IL-2 in patients with locally advanced
rectal cancer.