In recent years, PD-1/L1 inhibitors have attacked various cancers, as if they have become synonymous with immunotherapy, even if they are very knowledgeable about the background knowledge of the singularity cake, will subconsciously feel that "immunotherapy = PD-1 / L1 inhibitors"
However, as an immune checkpoint inhibitor, PD-1/L1 inhibitor can only be said to be the fastest developing and hottest class of drugs in immunotherapy, and there are still many things that cannot be done, and it needs to work hand in hand with other immunotherapy methods.
A recent clinical Phase I/II study published in Nature Medicine highlights the value of immune-modulatory vaccines: the active vaccine IO102/IO103, which targets IDO and PD-L1 in combination with navulilizumab, has an objective response rate (ORR) of up to 80%!
The combination of immunomodulatory vaccine plus PD-1 inhibitors not only significantly shrinks the tumor, but also brings the patient's median progression-free survival (PFS) to 26 months. The current clinical standard treatment plan for PD-1 inhibitors single drug or combined with CTLA-4 inhibitors is basically inferior in the face of such excellent efficacy data[1].
So the question naturally arises: why does the "immunomodulatory vaccine" of IO102/IO103 work so well?
Readers and friends whose brains are spinning fast will surely guess that it is because it can target IDO. The full name of IDO is indoleamine 2,3-dioxolase, which is also an important immunomodulatory molecule in the tumor microenvironment, and most of the time also plays a negative immunomodulatory role in "tethering" the immune system.
In the tumor microenvironment, there is a group of "IDO-specific" cytotoxic CD8+ T cells, which are activated by the IDO1 antigen introduced by the peptide vaccine, which will kill cancer cells and immunosuppressive cells with positive IDO expression in the microenvironment, thereby reversing the microenvironmental state and enhancing the anti-tumor immune response [2-3].
IDO-based vaccines activate specific T cells, kill cancer cells, and partial antigen-presenting cells
(Image source: Cancer Immunology, Immunotherapy)
The PD-1/L1 inhibitor "immune partner", which can reverse the microenvironment and enhance the immune response, if the treatment is safe and efficient, there is absolutely no stage. Although the combined program of PD-1 inhibitors + CTLA-4 inhibitors has long been approved in foreign countries for many indications, side effects are a major bottleneck, and theoretical safety is not as good as vaccines.
IO102/IO103, an immunomodulatory vaccine, is an immune companion by targeting both IDO and PD-L1. The results of the Clinical Phase I/II study published this time were published as the results of the Blockbuster Study Abstract (LBA) at the annual meeting of the European Society of Oncology (ESMO) last year, and the paper further improved and supplemented the data.
A total of 30 patients with metastatic melanoma were included in the study, all of whom had received at least 3 doses of IO102/IO103 vaccine injection and navuliyumab, and as of this data lock and median follow-up time of 22.9 months, 6 patients were still receiving treatment.
For the efficacy data, the singularity cake must be praised: the investigators evaluated an ORR of 80%, of which 13 patients (43%) were in complete remission, compared with the historical data of PD-1 inhibitor monotherapy, the objective response of IO102/IO103 + PD-1 inhibitor therapy increased by 5 times (OR=5.3)!
A complete/partial response was observed in patients with positive or negative PD-L1 expression at baseline, and 87% had a response lasting 12 months, and a median PFS of up to 26 months was much better than the 8.3 months of historical data. The median overall survival (OS) of all patients was not reached, with a 12-month survival rate of 81.6%.
As a clinical Phase I/II study, safety is actually the main endpoint of this study, and most of the adverse events reported by patients were mild-moderate, and only 4 patients reported grade 3-4 adverse events, and the incidence was basically the same as that of PD-1 inhibitor monotherapy.
The researchers also analyzed the immune response of patients after injecting the IO102/IO103 vaccine and found that in all 30 patients, 28 abnormal weekly blood could detect IDO-specific T cells and 26 cases could detect PD-L1-specific T cells, which was the real hammer of the vaccine to effectively activate the specific immune response.
In fact, the vaccine can also activate some IDO-specific CD4+ T cells, and the effect needs to be evaluated
The research team used the term "amazing efficacy" in the paper to describe the performance of the combination of IO102/IO103 vaccine + PD-1 inhibitors, which is indeed not an exaggeration. Based on its excellent efficacy, the US FDA has awarded IO102/103 "breakthrough therapy" certification at the end of 2020, which means that its future development will also lead to a green light.
Not long ago, the research and development company of IO102/103 has announced that it will launch a clinical phase III key study of this vaccine in combination with the PD-1 inhibitor perbolizumab for the treatment of metastatic melanoma, and the study is head-to-head design, directly with the treatment of pambolizumab monotherapy.
If this research can be successful, the immunotherapy pattern of melanoma will change, and it is only a matter of time before it is promoted to more cancers in the future. Strong vaccine, highly effective anti-cancer, this day Singularity Cake is really long awaited.
bibliography:
1.Kjeldsen J W, Lorentzen C L, Martinenaite E, et al. A phase 1/2 trial of an immune-modulatory vaccine against IDO/PD-L1 in combination with nivolumab in metastatic melanoma[J]. Nature Medicine, 2021.
2.Andersen M H. The specific targeting of immune regulation: T-cell responses against Indoleamine 2, 3-dioxygenase[J]. Cancer Immunology, Immunotherapy, 2012, 61(8): 1289-1297.
3.Dey S, Sutanto-Ward E, Kopp K L, et al. Peptide vaccination directed against IDO1-expressing immune cells elicits CD8+ and CD4+ T-cell-mediated antitumor immunity and enhanced anti-PD1 responses[J]. Journal for Immunotherapy of Cancer, 2020, 8(2).
The author of this article 丨 Tan Shuo