AACR 2020 – Changing the Immunotherapy Paradigm
By Ruchi Jhonsa, Ph.D.
While immunotherapy drugs have taken over the chemotherapy market to combat cancer, some limitations of the therapy, including tumor resistance and heterogeneity, have impacted their extensive use. Several combination therapies involving immunotherapies, chemotherapies, and targeted therapies have emerged in the recent past to counter these limitations. The inaugural day of the virtual AACR meeting highlighted some of these novel combination therapies that are currently changing the paradigm.
Anti-PVRIG Therapy, COM701 Augments anti-PD1 Response
The immune system is made up of a battery of regulatory proteins known as checkpoint inhibitors that enable it to distinguish self from non-self. These regulatory proteins interact with ligands on self-cells and send a negative signal to the T cells to prevent them from raising an immune response. However, these ligands are also present on the cancer cells, which enables them to evade immune recognition and attack.
Previously, two such regulatory proteins were identified, namely, CTLA-4 and PD-1, which helped cancer cells hide. A number of immunotherapies were developed against the two to enhance the immune response against cancer cells. But these therapies don’t necessarily work in all the patients. Besides, resistance is developed in patients on whom it does work initially. Soon, additional regulatory proteins like DNAM-1, TIGIT, and PVRIG, which make the immune system unresponsive to cancer cells, were discovered. While DNAM-1 stimulates the immune system, the other two counteract DNAM-1 and suppress the immune system.
The preliminary study presented by Dr. Ryan Sullivan, Assistant Professor of Medicine at Harvard Medical School and MGH Cancer Center underscored the importance of PVRIG receptor inhibition alongside anti-PD1 agents for cancer treatment. The study presented is a phase I clinical trial evaluating the safety and antitumor activity of a novel first in class immune checkpoint inhibitor, COM701, an inhibitor of PVRIG alone or in combination with nivolumab in a variety of cancer types.
This study is based on a very promising preclinical data where COM701 monotherapy or combination therapy with anti-PD1 or anti-TIGIT agents effectively suppressed tumor growth and activated T-cells in the vicinity of tumor cells in mouse models. COM701 was mostly well tolerated with a manageable safety profile both as a single agent as well as combo therapy.
Confirmed partial Response was observed in 2 patients; one in a 63-year old with primary peritoneal cancer treated with 20mg/Kg COM701 monotherapy every 4 weeks and another in 66-year old with metastatic CRC harboring KRAS mutation treated with COM701, nivolumab combo therapy every 3 weeks. Additionally, the tumor disease control rate of 69% in monotherapy arm and 75% in combo therapy arm was determined in diverse tumor types. Dr. Sullivan noted that 2 patients on single-agent and 4 patients on combo therapy have stable disease lasting for greater than 6 months. With the exciting preliminary Phase 1 results, the authors plan to launch dose expansion studies in patients with NSCLC, OVCA, breast, endometrial, and MSS-CRC cancer types.
Immune System Activation with OX40 Ligand Can Increase anti-PD-1 Efficacy
While Dr. Sullivan’s data supported the need for suppressing immune checkpoint proteins like PVRIG for augmenting anti-PD1 anti-tumor activity, Dr. Jimeno underscored the importance of activating immune checkpoint proteins like OX40, a tumor necrosis factor receptor family member for generating optimal T cell response.
OX40 is a secondary co-stimulatory immune checkpoint molecule present on the surface of activated T lymphocytes and NK cells. Its ligand OX40L is stably expressed in many antigen-presenting cells, such as macrophages and activated B-lymphocytes. OX40 signaling enables CD4+ and CD8+ T cells to survive and expand, enhance memory responses, and inhibit regulatory T cell function. Augmenting signals through OX40 have shown great therapeutic efficacy in models of cancer.
Dr. Antonio Jimeno from the University of Colorado Cancer Center presented clinical data for novel mRNA-based lipid nanoparticle therapeutic agent named as mRNA-2416 that expresses the wild type human OX40L. By directly inserting the beads inside the tumor, the group plans to activate OX40 signaling locally. Unpublished preclinical data showed promising anti-tumor activity for mRNA-2416. Based on this data, the clinical study is testing the safety and efficacy of mRNA-2416 administered directly in the tumor every 2 weeks in a standard 3+3 phase I dose-escalation in patients with locally, advanced, or metastatic solid malignancy or lymphoma.
Out of the 39 patients enrolled in the study, 14 achieved the best overall response of stable disease, of which 6 had stable disease for more than 14 weeks, and 4 had tumor shrinkage in the injected lesions. The injected tumors showed prominent expression of OX40L ligand along with activation of pro-inflammatory gene expression responses, including cytolytic activity scores, elevated PD-L1 expression, and stimulation of a T cell inflamed gene expression profile indicative of PD-1/L1 Response. On an exciting note, Dr. Jimeno concluded the presentation by mentioning about the Part B of the study, which will jointly evaluate mRNA-2416 and anti-PD-L1 agent durvalumab in solid tumors with a focus on advanced ovarian carcinoma.
HPV Vaccine to Intensify Keytruda’s anti-Cancer Response
Human papillomavirus (HPV) is a sexually transmitted virus that could cause cervical cancer in women. According to the WHO, two HPV types (16 and 18) cause 70% of cervical cancers and precancerous cervical lesions. Currently, USFDA approved treatment with Pembrolizumab (Keytruda) shows an objective response rate of 12.2% in PD-1 negative and 14.6% in PD-1 positive cervical cancers.
To augment the Response of pembrolizumab to cervical cancers, a group of scientists from Genexine Inc, a South Korean biotechnology company, are studying a combination of the HPV vaccine, GX-188E with pembrolizumab monotherapy in patients with advanced or metastatic cervical cancer. The rationale being that the addition of the HPV vaccine will boost the antigen-specific T cell responses intensifying the anti-tumor Response of pembrolizumab.
This open-label study includes 36 women who have advanced or metastatic cervical cancer and have failed to respond to all available standard of care treatments. Patients in this study received GX-188E 2mg intramuscularly (at weeks 1,2, 4,7, 13, 19, and 46) + pembro 200mg (every 3 weeks) for up to 2 years or until progression.
According to the interim analysis presented by Dr. Jung Won Woo, executive vice president of Genexine Inc, the objective response rate of 45.5% with 5 confirmed responses and five partial responses were observed. Further, the median progression-free survival of 4.1 months was observed with the combo. Treatment with the combo activated the host immune cells like antigen-specific T cells in 78.3% patients, demonstrating the effectiveness of the vaccine.
Additionally, the safety profile of the drug was found manageable and comparable to that of pembrolizumab monotherapy. Dr. Woo noted that in contrast to pembrolizumab alone, combined therapy was much more effective in tumors negative for PD-L1 expression. Although the combination is much effective than anti-PD-L1 monotherapy, the authors concluded that larger clinical trials are warranted for the combo therapy to further test the antitumor Response and antigen-specific immune response of the drug.
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