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October 13, 2022 / eMedClub News / -- TILT Biotherapeutics recently announced its oncolytic adenovirus candidate TILT-123 Completed the first phase 1 clinical dosing with Merck PD-1 monoclonal antibody KEYTRUDA (pembrolizumab) for the treatment of platinum-resistant or refractory ovarian cancer patients
.
This is an open-label, dose-escalating, multicenter, multi-country clinical trial involving 15 oncology patients to evaluate the safety and efficacy
of TILT-123 in combination with KEYTRUDA in patients with platinum-resistant and refractory ovarian cancer.
In addition, the company's open Phase I clinical programs in Europe and the United States now cover multiple cancer types, including ovarian, head and neck and melanoma
.
In September, the company also entered into a new collaboration and supply agreement with Merck to evaluate the efficacy
of TILT-123 in combination with KEYTRUDA in patients with immune checkpoint inhibitor-refractory non-small cell lung cancer.
Keytruda is Merck's flagship monoclonal antibody product, which has been approved by the FDA to treat more than 30 cancer types, and this combination with oncolytic virus immunotherapy means that Merck is further deepening the commercialization value of Keytruda and exploring other promising and innovative treatment opportunities to benefit
more patients.
TILT-123, a candidate for TILT Biotherapeutics, is an engineered human 5/3 chimeric adenovirus that not only replicates inside tumors, lyses tumors and releases tumor-associated antigens, but also produces the immune-stimulating cytokines TNFα and IL-2
.
These factors can not only stimulate the replication of the virus, but also achieve the effect
of further activating the T cell immune response.
Another advantage of the virus is that it does not multiply in normal cells and can be administered
intra-tumor or intravenously.
It is worth mentioning that in preclinical models, its significant efficacy
has been confirmed.
The data showed that TILT-123 therapy, alone and in combination with other immunotherapy drugs such as T cells and checkpoint inhibitors, showed a 100% response rate
.
▲ The mechanism of action of TILT-123 (Image source: TILT).
.
Notably, at the heart of TILT's innovative approach is the use of cancer-specific oncolytic adenoviruses, armed with cytokines and other molecules, to enhance the patient's T-cell immune response
.
That is, foreign genes are inserted into the virus sequence to enable them to express tumor antigen antibodies/immune-activating cytokines, etc.
, this modification strategy is generally called armored oncolytic virus, loading the virus itself with new "weapons" to achieve better killing effects
.
▲ TILT-123 virus construct (Image source: TILT) Based on this strategy, the company has established a number of related research and development pipelines, including TILT-234, TILT-452, TILT-321 At present, several candidate therapies are still in the preclinical development stage
.
Among them, in September 2019, TILT Biotherapeutics published the positive results achieved by TILT-452 in preclinical studies and published the data in the journal Frontiers in Immunology
.
TILT-452 is also a 5/3 serotype chimeric adenovirus
engineered to express the IL-2 variant.
Preclinical studies showed that 62.
5% of pancreatic cancer hamsters receiving TILT-452 monotherapy showed long-term complete remission and significantly longer
survival compared with controls.
At the same time, the study also showed that TILT-452 can change the tumor microenvironment, promote the penetration of certain T cells in the tumor microenvironment and the high expression
of MHC-II.
▲ TILT-452 monotherapy for pancreatic cancer in a mouse model (Image source: Reference 2).
epilogue
As one of the sharp tools of tumor immunotherapy, oncolytic virus has a history of 100 years, but it has not been paid attentionto in the early stage due to poor effect and large side effects due to technical limitations.
In recent years, with the development of virology and genetic engineering technology, scientists can modify viral genes, and constantly improve and update them, and today's oncolytic virus therapy has the advantages of high killing efficiency, good targeting, small side effects, multiple ways to kill tumors and low cost, which has become a promising development direction
in the field of tumor immunity.
In addition, with the deepening of research, the development of combination therapy of oncolytic virus and other immunotherapy to enhance the killing power of tumors has also become a hot research direction
in the field of oncolytic viruses.
Moreover, the administration of oncolytic virus has gradually broken through from local/intratumoral injection to intravenous administration, which can be seen that the therapy is gradually getting better
.
At present, the research and development of oncolytic viruses at home and abroad is also in full swing, and many companies are actively deploying related research and development
in this field.
The rapid progress in China has also entered phase 3 clinical trials
.
It is believed that the continuous innovation of technology will promote more oncolytic virus drugs to clinical application and benefit more patients
.
Resources:
1.
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https://mp.
weixin.
qq.
com
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