A few reminders for the application of PD-1 inhibitors

Possible side effects of PD-1 inhibitors

The overall side effects of PD-1 inhibitors are much smaller than traditional radiotherapy and chemotherapy. The most common side effect is "flu"-like performance: fever, fatigue, dizziness, body muscle aches, lethargy, etc. The incidence rate is about 30%.

In addition, approximately 5%-10% of patients will have severe immune-related inflammatory reactions: thyroid inflammation (such as hyperthyroidism or hypothyroidism), immune pneumonia, immune enteritis, immune hepatitis or even immune myocarditis, immune inflammation. All should be handled properly and in time.

How to evaluate the efficacy of a PD-1 inhibitor?

For the vast majority of solid tumors (except lymphoma), the average duration of onset of PD-1 inhibitors is approximately 2-4 months. Therefore, after taking the drug, patients should better take a check-up every 6-8 weeks.

Imaging suggests that the tumor is shrinking or stable so as to determine if it’s appropriate to continue using PD-1 inhibitors. If imaging suggests that the tumor is enlarged, but the patient's general condition is acceptable, patients can take the drug 2-3 times to see the effect, because about 10% of patients will have "false progress".

What are false progress and mixed reactions?

Some patients, after receiving PD-1 inhibitor treatment, are first observed to have increased tumor size, which then gradually reduced. This is a false progress.

How to predict and judge "false progress"? At present, it is mainly through comprehensive changes in patients' symptoms, changes in tumor markers, changes in SUV on PET-CT, changes in cytokine IL-8, and changes in ctDNA content. The most accurate way is to puncture suspicious lesions for biopsy. If the biopsy proves to be all cancer cells, it should be considered as true progress; if there are a large number of infiltrating lymphocytes, immune cells, it is highly suspected to be a false progress.

Some patients, after receiving PD-1 inhibitor treatment, some of the lesions in the body shrink, and some of the lesions increase, which is called the mixed response.

The root cause of this situation is that the lesions in different parts of a patient have different sensitivities to the drug, which is called heterogeneity. When this happens, it’s better to consider adding a little local treatment (intervention, radiofrequency, particle implantation, radiotherapy) to the enlarged lesions, or in combination with other treatments.

What are the precautions for the use of PD-1 inhibitors?

First of all, the following patients are not suitable for the use of PD-1 inhibitors: bedridden patients; patients with acute bacterial infections but still uncontrolled; patients who have undergone liver transplantation, kidney transplantation; patients with systematic autoimmune diseases such as lupus erythematosus, Behcet's disease, Sjogren's syndrome, vasculitis; patients with MDM2 amplification, EGFR mutation, JAK mutation, etc.

Secondly, before using PD-1 inhibitors, it is generally recommended to have the following tests: blood routine, liver and kidney function, electrolytes, blood clotting, thyroid function, electrocardiogram, abdominal B-ultrasound and chest X-ray.

Last but not least: a growing evidence supports that immunotherapy, such as PD-1 inhibitors, should be used as early as possible. Currently, PD-1 inhibitors have been approved for consolidation therapy after local advanced malignant melanoma surgery; PD-1 inhibitors are used for consolidation therapy of non-small cell lung cancer after radical chemoradiotherapy, and phase III clinical trials all prove that the survival period has increased several times.

How to overcome PD-1 inhibitor resistance?

PD-1 inhibitors generally have a long-lasting effect on patients who respond effectively to them; however, it has been observed that about 30% of patients have developed disease resistance. The key to overcoming drug resistance is:

First, if possible, identify a new or growing resistance site and use a needle biopsy and in-depth immunoassay to find the cause of the drug, then treat differently according to the reasons. For example, some patients are compensated for high expression of TIM-3, LAG-3 or IDO; then, the best choice is PD-1 inhibitor combined with TIM-3 inhibitor, LAG-3 antibody, IDO inhibitor.

Secondly, for patients who cannot identify the cause of drug resistance, it’s better to adopt combined therapy in a hope to reverse the drug resistance, prolong the survival period.

Tumor immunotherapy mainly includes the following categories:
(1) Immune checkpoint inhibitors: Targets such as IDO, LAG-3, VISTA Inhibitor, ICOS Inhibitor, CD39 Inhibitor and TIM-3 are the most studied.

(2) Oncolytic virus (T-VEC is available on the market): The oncolytic viruses of herpes simplex virus, adenovirus, poxvirus, and M1 virus are constantly being optimized and improved.

(3) Tumor vaccine: Personalized immunization vaccine based on nascent antigen is very promising; peptide or RNA vaccine based on HPV, EBV and other viral antigens needs to be combined with drugs such as PD-1 inhibitor; other vaccines are still under development.

(4) Immune cell therapy: There are certain prospects for specific immune cell therapy, such as CAR-T and TCR-T, which require genetic modification of immune cells in vitro. CAR-T treatment of blood cancer has been listed in the US. There are also preliminary data on the treatment of synovial sarcoma and malignant melanoma using TCR- T. However, CIK, DC-CIK, NKT, NK, DC and other non-genetically modified, non-specific tumor immune cell therapy are basically ineffective.

(5) Cytokines: Several anti-cancer interleukins such as IL-2, IL-10, IL-12, IL-15, IL-21 have been modified to be used alone or in combination with PD-1 inhibitors. There is a certain prospect for such therapy but still in the early stages.