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Combination application is currently a research hotspot for resistance and reversal of immune resistance
Written by丨Lu Xiong
In recent years, immunotherapy has been widely used in the field of cancer treatment worldwide, and immune checkpoint inhibitors (ICIs) represented by PD-1/PD-L1 monoclonal antibodies have been approved for use in many cancer types, bringing long-term survival benefits to some cancer patients. However, similar to other antineoplastic drug treatment modes such as chemotherapy and targeted therapy, immunotherapy can also cause drug resistance.
Classification of immunotherapy resistance
▌Primary drug resistance:
The general biology of primary resistance to immunotherapy is defined as the inability of immune cells to develop an anti-tumor response upon initial exposure to a drug. Among them, PD-L1 inhibitors have a long circulating half-life, repeated dosing every 2-4 weeks, and no significant differences in efficacy or toxicity have been found at doses greater than 1 mg/kg, and based on these data, some physicians believe that two cycles of treatment are sufficient to evaluate primary resistance.
▌Secondary drug resistance:
In general, secondary resistance refers to the condition that occurs when a patient receives antineoplastic therapy, has a documented, confirmed objective response, or has long-term stable disease (SD, > 6 months), and then develops disease progression with continued treatment. This type of resistance may occur through the adaptation of tumor cells, or it may arise through clonal selection or clonal evolution of tumor cells, which contain genetic changes that confer therapeutic resistance to clones.
Why is immunotherapy resistant?
(1) Internal factors of tumor cells: such as loss of antigen expression, less neoantigen, low TMB, defective antigen presentation, endogenous T cell clearance, MAPK pathway activation, PTEN deletion, Wnt signaling pathway activation, low PD-L1 expression, no response to T cells, etc.;
(2) External factors of tumor cells: such as T cell deficiency, cold tumor, immunosuppressive microenvironment, inhibitory immune checkpoints, TIM-3 upregulation, immunosuppressive molecules, IDO upregulation, TGF-B upregulation, CD73 upregulation, immunosuppressive cells, increase in MDSC, expression of specific driver genes, low Teff gene tag, intestinal microbial disorders, etc. [1].
Table 1 Mechanism of immune resistance to PD-1 at immune checkpoints[2]
Regimens to address resistance to immune checkpoint PD-1/PD-L1 inhibitors
■In combination with chemotherapy[2]
In the treatment of solid tumors and lymphomas, the combination of PD-1 inhibitors with chemotherapy has achieved good results. On the other hand, patients with relapsed and refractory Hodgkin lymphoma who have failed anti-PD-1 therapy appear to benefit from conventional salvage chemotherapy therapy.
Clinically, cetuximab combined with paclitaxel has been shown to be effective and safe in recurrent or metastatic head and neck squamous cell carcinoma that has progressed after immunotherapy, and cyclophosphamide combined with vinorelbine can activate stem CD8+ T cells and improve the anti-PD-1 efficacy of triple-negative breast cancer.
■In combination with anti-angiogenic drugs
Anti-angiogenic drugs have been shown to have immunomodulatory effects in the tumor microenvironment. At the same time, tumor vascular normalization can remodel TME and transform TME from immunosuppressive to immunosupportive.
The KEYNOTE-146 study is designed to evaluate the efficacy of lenvatinib + pembrolizumab in patients with metastatic renal cell carcinoma who have failed prior immunotherapy. A total of 145 patients were enrolled and 104 had been treated with ICIs. Fifty-eight (55.8%) of the patients had an objective response at week 24, and the incidence of grade 3 to 4 adverse reactions was low. Lenvatinib + pembrolizumab showed good anti-tumor activity and a manageable safety profile, and this regimen may be an option for the treatment of metastatic renal cell carcinoma after ICIs resistance.
■In combination with radiotherapy
Radiotherapy can directly act on the DNA of tumor cells to kill cells, or it can alter the tumor microenvironment, induce immune activation, elicit anti-tumor responses, and induce tumor regression in non-irradiated areas by producing orthotopic tumor vaccines.
■In combination with CTLA-4 monoclonal antibody
CTLA-4 has a different mechanism of action from PD-1 and plays a complementary role in regulating the adaptive immune response. PD-1 depletes peripheral T cells, while CTLA-4 mainly plays an inhibitory role in the early stage of T cell activation, so anti-CTLA-4 antibodies can synergize with the clinical effects of anti-PD-1 antibodies. There have been clinical trials that have demonstrated that the double-immunization combination therapy has a higher response rate and a comparable safety profile, but the clinical studies of its application after immunotherapy resistance have just begun.
■In combination with other novel immune checkpoint inhibitors
In recent years, research into the blockade of novel immune checkpoints and their ligands is ongoing. T cell immune receptors with immunoglobulin and immunoreceptor tyrosine inhibitory motif (ITIM) domains are a promising new target for cancer immunotherapy.
■Combined with intestinal microbial transplantation
The composition of the gut microbiota has a significant impact on the efficacy of ICIs and helps to improve the therapeutic activity of ICIs. A clinical trial evaluating the safety and efficacy of fecal microbiota transplantation (FMT) in combination with anti-PD-1 in patients with PD-1-refractory melanoma showed clinical benefit in 6 of 15 patients.
■Combined with HER2 targeting
Communication between immune checkpoints and their response ligands is achieved by targeting a large number of signaling axes. Activation of human epidermal growth factor receptor 2 (HER2) leads to numerous oncogenic signaling axes, particularly phosphatidylinositol-3-kinase (PI3K)/Akt pathway activation, which weakens T cell activation and resulting anti-tumor immunity.
The study found that the combination of nivolumab + trastuzumab could improve the progression-free survival of gastric cancer patients, and 17 of the 92 patients with HER2-positive gastroesophageal adenocarcinoma who received the new anti-HER2 monoclonal antibody magatuximab in combination with pembrolizumab had an objective response, showing certain efficacy benefits and acceptable safety.
Bibliography:
[1] Ilaria Attili, et al.,Strategies to overcome resistance to immune checkpoint blockade in lung cancer, Lung Cancer 154 (2021) 151–160
[2] Mechanism of immune resistance in tumors based on immune checkpoint PD-1 and strategies for retreatment after drug resistance
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