The revival of therapeutic tumor vaccines! What are the results of the clinical trials of the mRNA vaccine giants?

Vaccines against human papillomavirus (HPV) and hepatitis B virus have been successfully applied to the prevention of related tumors

However, since 2010, sipuleucel-T (Note: a DC vaccine that separates the patient's DC cells from the blood, activates it outside the body, and then returns it to the patient) has been approved by the FDA for the treatment of prostate cancer (Note: Compared with the control group, the survival period of patients in the vaccine treatment group was only extended by about 4 months), no therapeutic tumor vaccine was approved for marketing, and a series of clinical studies had negative results

sipuleucel-T, the picture comes from the Internet

Failure is the mother of success, scientists never give up

Analyzing the reasons, the early therapeutic tumor vaccines simply thought that it was to supplement the host with tumor-reactive T cells, ignoring the immune resistance (internal) of tumor cells and local and systemic immunosuppression (external)

Technology continues to improve, select tumor antigens are the focus of the preparation of a vaccine, there are mainly three types: First, the new antigen vaccine (neoantigen vaccines): for a tumor antigen mutation produced a large extent, the success of new individualized vaccine antigens It depends on the tumor mutation burden (TMB) and the accuracy of antigen screening; 2.

In April 2021, Nature Reviews Cancer published a review, summarizing in detail some important reasons and thinking about the failure of tumor vaccines in the past

In recent years, the treatment of immune checkpoint inhibitors (ICIs) represented by PD-1 inhibitors has become a milestone in tumor treatment

The outbreak of the new crown epidemic has left a strong mark in the history of the development of mRNA vaccines, and it has also made the three giants of mRNA vaccines infinite

BioNTech

BNT 111 [2]

A nano-scale liposomal mRNA vaccine that encodes 4 non-mutated tumor-associated antigens (TAA), including: NY-ESO-1, MAGE-A3, tyrosinase, TPTE, these antigens have limited expression in normal tissues, but in melanin Tumors are very common and highly immunogenic

After vaccination, the patient's spleen metabolic activity increased, and the plasma levels of inflammatory cytokines (IFN-α, IFN-γ, IL-6, CXCL10, IL-12p70) increased

Some patients were vaccinated with BNT111 after the PD-1 inhibitor treatment failed, and the tumor retreated.

BNT 122 [3]

A cationic lipid complex (lipoplex) mRNA neoantigen vaccine

16% of patients discontinued the drug due to PD during treatment

NEO-PV-01 [4]

A phase Ib study of a personalized neoantigen vaccine NEO-PV-01 combined with nivolumab in the treatment of advanced solid tumors (trial number: NCT02897765)

The patient received nivolumab for 12 weeks first, and then received NEO-PV-01 vaccination

In terms of safety, the most common adverse reactions after vaccination are injection site reactions (52%) and influenza-like reactions (35%).

Moderna

mRNA-4157 [5]

It is a lipid-encapsulated mRNA personalized neoantigen vaccine.

A total of 79 patients were enrolled in the study, 16 were treated with single drugs, and 63 were treated with pembrolizumab

mRNA-5671

This is an mRNA neoantigen vaccine against KRAS mutations.
It has now entered the phase I clinical study (trial number: NCT03948763).
It evaluates mRNA in patients with KRAS mutations in progressive/metastatic NSCLC, colorectal cancer, and pancreatic cancer.
-5671 safety and tolerability
.
KRAS is one of the key regulators of cell differentiation and survival, and its mutation can lead to abnormal cell differentiation and regulation
.

KRAS mutation is one of the common tumor-causing genes, which can be found in pancreatic cancer, lung cancer, colorectal cancer, etc.
The four most common mutation sites associated with tumorigenesis include: G12D, G12V, G13D, G12C (accounting for KRAS mutations) 80%~90%)
.
Preclinical studies have shown that after injection of KRAS mRNA vaccine, CD8+ T cell activity is significantly increased
.

CureVac

CV9202 [6]

It is an mRNA vaccine that encodes 6 non-mutated tumor-associated antigens of NSCLC, including: NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, MUC-1
.
This is a phase Ib clinical trial (trial number: NCT01915524), which included 26 patients with stage IV NSCLC who had PR or SD after standard first-line treatment and were given CV9202 combined with local radiotherapy
.

The patients were divided into three groups: 1.
Non-squamous NSCLC, no EGFR mutation, PR/SD after 4 cycles of platinum-based and pemetrexed treatment (n=16); 2.
Squamous NSCLC, platinum or non-platinum PR/SD after ≥4 cycles of similar treatment (n=8); Third, non-squamous NSCLC, with EGFR mutation, after receiving EGFR-TKI treatment (≥3 months, ≤6 months) PR/SD (n=2 )
.
One and three continue to be given pemetrexed or EGFR-TKI treatment after receiving the vaccine treatment
.

The overall safety of treatment is good, and injection site reactions and flu-like symptoms are the most common CV9202-related adverse events
.
Three patients had CV9202 related adverse events (fatigue, fever) above grade 3
.
Compared with baseline, most patients (84%) had an increased CV9202 antigen-specific immune response, of which 80% of patients had increased levels of specific antibodies, 40% of patients had increased levels of functional T cells, and 57.
7% of target lesions The best effect is SD
.

Summarize

The basis of therapeutic tumor vaccines is a comprehensive understanding of the mechanism of tumor immunity
.
Whether a clinical trial succeeds or fails, it can bring us more information for reference
.
On the one hand, the quality of vaccine antigens needs to be improved; on the other hand, there is a need to improve delivery technology
.
Combined with traditional treatments (chemotherapy, radiotherapy) or other immunotherapy (such as PD-1 inhibitors, etc.
), it may be helpful to the problem of drug resistance in tumor treatment
.
There is still a long way to go for therapeutic tumor vaccines!

references

1.
Nat Rev Cancer.
2021; 21(6): 360-378.

2.
Nature.
2019; 565(7738): 240-245.

3.
https://cancerres.
aacrjournals.
org/content/80/16_Supplement/CT301

4.
Cell.
2020; 183(2): 347-362.
e24.

5.
https://jitc.
bmj.
com/content/8/Suppl_3/A477.
16.
J Immunother Cancer.
2019; 7(1):38.