The emergence of PD-1 antibodies and PD-L1 antibodies has rewritten the diagnosis and treatment guidelines for many solid tumors, and even rewritten the lives of many patients with middle and advanced cancer, so that more and more patients who were originally sentenced to death have regained their vitality.
However, there are still a large number of patients who have failed PD-1 treatment in clinical work:
- First, if left unchecked, the vast majority of advanced solid tumors are ineffective against PD-1 inhibitors, after all, the effectiveness of PD-1 in treating the vast majority of cancer types hovers around 20 percent;
- Second, even in patients who are effective at the beginning of treatment, some of them will develop drug resistance after a period of time.
For patients who have failed treatment with these PD-1 inhibitors, what should be the next treatment? This is the focus of research in recent years, in fact, the main ideas are nothing more than two:
(1) Return to traditional treatment
Before the emergence of immunotherapy such as PD-1 inhibitors, all kinds of cancers have traditional treatments such as chemotherapy and targeted therapy, and since PD-1 inhibitor therapy is ineffective or failed, returning to the original traditional treatment is the mainstream idea in most cases.
For example, advanced non-small cell lung cancer with failed PD-1 inhibitor therapy can be considered for chemotherapy, anti-angiogenesis drugs can be considered, and specific targeted therapy can be tried for a very small number of patients with concomitant driver gene mutations.
Several retrospective studies have shown that patients with advanced solid tumors who have failed PD-1 inhibitor therapy have sometimes been more effective than in the historical record after receiving traditional treatments such as chemotherapy. For example, the effective rate of single-agent docetaxel in the treatment of advanced non-small cell lung cancer is generally less than 20%, but a number of retrospective studies have shown that patients with advanced lung cancer after the failure of PD-1 antibody monotherapy or PD-1 antibody combined with first-line chemotherapy can be as effective as 30% or more. This phenomenon has been reported in lung cancer, urinary tract carcinoma, head and neck squamous cell carcinoma and other solid tumors.
(2) Find a way to start the body's anti-cancer immune response again and restore the sensitivity of immunotherapy
For example, stereotactic radiotherapy is performed on suitable lesions to reduce tumor burden while releasing antigens and restore the sensitivity of PD-1 inhibitors (for details, see: Inexpensive stereotactic radiotherapy: cure oligomettasis, sensitized PD-1);
For example, with the addition of CTLA-4 antibodies, LAG-3 antibodies, oncolytic viruses, tumor vaccines and other immunotherapeutic means, the sensitivity of PD-1 antibodies is restored;
Another example is to try other new combinations of immunotherapy. Recently, a new combination therapy has appeared, that is, the targeted drug dasatinib combined with dendritic cell vaccine.
Professor Walter J Storkus of the Pittsburgh School of Medicine has developed a new dendritic cell vaccine, which targets antigens that are not directly derived from special proteins with high expression on cancer cells, but special proteins with high expression on the vascular endothelium in tumor tissue, such as DLK1, EphA2, HBB, NRP1, RGS5 and TEM1.
These proteins are particularly expressed on the vascular endothelium of tumor tissue, but not much in the vascular endothelium of normal tissue. Therefore, guiding the immune system to attack these proteins can destroy the blood vessels that supply cancer cells with the ability to supply capacity and nutrition, thereby exerting anti-cancer effects. Numerous studies have shown that dasatinib has the function of increasing immune cell infiltration, so it can be combined with dendritic cell vaccines.
In a prospective clinical trial conducted by Professor Walter J Storkus, a total of 15 patients with advanced malignant melanoma who failed PD-1 inhibitor therapy were treated with dasatinib (70 mg once, twice a day) in combination with the novel dendritic cell vaccine, and all patients were divided into two groups:
- One group received vaccine treatment first, and oral dasatinib therapy began in the fifth week;
- The other group received a combination of dasatinib and vaccine from the start.
13 patients with evaluable efficacy: 4 patients had significant tumor remission and 3 patients had stable tumors – and patients who had taken dasatinib orally at the outset were more effective (66.7% vs 0%), had a longer survival (19.1 months vs. 8.3 months), and among those who had been onactive, the longest maintenance of efficacy had been more than 2 years.
In addition, the protocol not only has an effect on malignant melanoma, but also the domestic research team has found in animal tests that it may also have an effect on other solid tumors, including breast cancer.
The figure above shows that compared with untreated mice and breast cancer mice receiving dasatinib alone and dendritic cell vaccine alone, and rats receiving a combination of dasatinib and dendritic cell vaccines, tumor growth was significantly slower and survival was significantly longer.
bibliography:
[1]. Dendriticcell vaccines targeting tumor blood vessel antigens in combination withdasatinib induce therapeutic immune responses in patients withcheckpoint-refractory advanced melanoma. J Immunother Cancer. 2021Nov;9(11):e003675
[2]. Synergisticanti-tumor effects of dasatinib and dendritic cell vaccine on metastatic breastcancer in a mouse model. Oncol Lett. 2018 May;15(5):6831-6838