Cancer Gene Therapy

Gene Therapies of Cancer – First Few of The Upcoming Wave

Gene therapies are a targeted approach to cancer treatment. They are being developed for the types of cancers that have no effective treatment options.

The term cancer includes 100+ diseases that affect nearly every part of the human body. All cancers are potentially life threatening and hard to cure (1). Traditional treatments – surgery, radiation therapy, and chemotherapy – work in some cases, but not always.

Targeted therapies take advantage of molecular mechanisms unique to cancer cells. Gene therapies use genetically engineered viruses or modified immune cells to selectively destroy cancers based on their molecular properties.

Below are six approved cancer gene therapies, and three more that are likely to make it to the clinics in the near future.

Gendicine – The First Gene Therapy – Available in China Only

Gendicine is a gene therapy for head and neck cancers. It was approved by China Food and Drug Administration in 2003 (2). 

The science of Gendicine is based on tumor suppressor gene p53. This gene produces p53 protein that blocks cell division and initiates programmed cell death. Most human cancers have mutations in the p53 gene. It is how they grow uncontrollably.

In Gendicine p53 DNA is packaged in a replication deficient adenovirus. The virus is injected directly into tumors. It passes inside cell nuclei and restores expression of the p53 protein.

According to one estimate by the year 2013 over 30,000 people were treated with Gendicine (2). The treatment produced 30-40% complete response and 50-60% partial response, with combined response rate near 90%.

Patients from all over the world travel to China to get Gendicine treatment. Doctors in the West advise against it. They do not trust the Chinese (3, 4).

Gendicine Gene Therapy Summary

Oncorine – The First Oncolytic Virus on the Market

In traditional gene therapy viruses are used as vehicles for gene delivery. Oncolytic viruses do not aim to deliver any genes. Instead they are engineered to preferentially replicate in cancer cells. Successive rounds of viral replication start destroying the cancer. The remains of cancer cell breakdown alert the immune system that tracks down and kills what is left.

Oncorine was the first oncolytic virus on the market. It was approved in 2005 by China Food and Drug Administration for the treatment of nasopharyngeal carcinoma (5).

It is an adenovirus with two deleted genes, one of which is E1B-55K. The role of this gene in the wild type virus is to block the host p53 pathway mentioned above. When the virus without E1B-55K enters a healthy cell the p53 protein gets activated, the cell dies, and viral spread is prevented. In cancer cells lacking p53 activity oncorine virus goes through rounds of replication, destroying the tumor.

In the Phase 3 of clinical trials oncorine combined with chemotherapy produced a response rate of 86%, while chemotherapy alone had a response rate of 59%. Complete response was achieved in 11% of the patients in the oncorine group, compared to 3.7% of the patients in the control group (5).

Nasopharyngeal carcinoma is a rare type of cancer affecting 1 in 100,000 people each year. In some parts of China the incidence rate is much higher, up to 21 times (6). The difference in incidence rate explains why there is no discussion about making oncorine available in other parts of the world.

Oncorine Gene Therapy Summary

T-Vec or Imlygic – Oncolytic Virus for Melanoma

T-Vec is the first oncolytic virus approved in the US. It is designed to treat melanoma, the most serious form of skin cancer that affects 70,000 people a year (7).

The biological agent of T-Vec is a modified herpes simplex virus type 1 (HSV1). In its native form this virus is widely spread among humans. It is hiding in neurons until it gets activated by some form of stress. Then it travels to skin cells and starts replicating, causing sores.

There are several genetic modifications that make T-Vec efficient at destroying cancer cells (7, 8). First is deletion of ICP34.5 gene. Similar to E1B-55K in Oncorine, this gene helps HSV1 to bypass cellular defence mechanisms that lead to apoptosis. Without ICP34.5 the virus cannot propagate in healthy cells. In cancer cells that have compromised apoptotic response T-Vec continues replicating and spreading. 

Second key modification is addition of gene encoding GM-CSF, a macrophage colony stimulating factor that increases tumor antigen presentation. T-Vec is often mentioned as immunotherapy because of its ability to activate anti-cancer immune response.

T-Vec is delivered directly into melanoma tumors through a series of injections. In Phase 3 clinical trials patients receiving T-Vec showed a durable response rate in 16% of the cases, compared to 2% in the control group (8).

Metastatic melanoma is considered to be one of the most difficult to treat cancers. T-Vec offers an additional option for patients who have not responded to surgery.

T-Vec Imlygic Gene Therapy Summary

Rexin-G – Approved in the Philippines – Struggling in the US

Rexin-G was approved in the Philippines in 2007 as a safe and effective drug for all solid tumors (9).

The viral particles in Rexin-G are designed to perform two functions – seek out tumors and stop cell replication. On the surface they carry SIG-targeting peptides that bind to Signature proteins in the tumor microenvironment. After infecting tumor cells the virus starts expressing human cyclin G1 protein that stops cell cycle and prevents cell division. 

Unlike the oncolytic viruses described above, Rexin-G is administered intravenously. It circulates around the body and accumulates in metastatic lesions (9).

In the US, five Phase 1 and 2 clinical trials were initiated in 2007 and completed in 2011 (10). Then for several years Rexin-G remained in obscurity. It resurfaced in 2019 under the name of DeltaRex-G. Apparently several patients from the US clinical trials survived, indicating the effectiveness of the therapy (11). 

In February 2020 the FDA approved expanded access to DeltaRex-G for patients with advanced pancreatic cancer and sarcoma (12). “Expanded access” means only access to experimental treatment. There is no mention of Phase 3 trials aiming to get approval of this therapy.

Rexin-G Gene Therapy Summary

Kymriah and Yescarta – CAR T-Cell Therapies for Leukemia

Kymriah and Yescarta are similar gene therapies that came to the US market at the end of 2017.

Both therapies use the patient’s own T cells to track down and kill B lymphocytes that became cancerous. The treatment consists of extracting T cells from a patient’s peripheral blood, modifying them so they can recognize the B cells, and reintroducing the modified T cells back into the bloodstream (13).

Genetic modification of T cells is done in a lab with a virus that delivers a gene for chimeric antigen receptor, or CAR. This receptor is made of an extracellular domain that recognizes CD19 antigens found on the surface of B cells, and an intracellular domain that initiates signalling cascade leading to T cell activation.

Once back in the patient, CAR T cells start chasing and killing B cells, eliminating the cancer.

Kymriah was demonstrated to be effective for the treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) and for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Such patients have no options, their life expectancy is measured in weeks or months. Kymriah treatment led to 82% overall remission rate for ALL and 52% for DLBCL (14).

Yescarta has been approved for the treatment of relapsed or refractory DLBCL. Objective response rate achieved in Yescarta trials was 72% (15).

At a first glance Kymriah and Yescarta look very similar. It would take a professional to decide which treatment option is better for a patient. 

Luckily now we have options. 

Kymriah and Yescarta Gene Therapy Summary

Cancer Gene Therapies in Phase 3 of Clinical Trials

Gene therapy is a new technology that is rapidly gaining momentum. Hundreds of new treatments are being investigated in clinical trials. But only a few prove to be safe and effective. 

Below are four cancer gene therapies that could make it to the market in the next couple of years.

ProstAtak is gene therapy for prostate cancer developed by Advantagene (16). It is a virus-based oncolytic therapy similar to the ones used in Oncorine and T-Vec. The therapeutic aim of ProstAtack is to prevent the recurrence of prostate cancer after initial treatment. In Phase 2 clinical trial patients treated with radiation therapy combined with ProstAtak had 10% cancer recurrence rate, compared to 30% in those treated with radiation therapy only. Advantagene is currently running Phase 3 trial to evaluate ProstAtak in a group of 711 men.

VB-111 is an anticancer agent aimed at treating solid tumors (17). It is an adenoviral vector carrying a gene for Fas/NFR cell death receptor. The death receptor expression is controlled by PPE-1-3x promoter, which gets activated only in angiogenic blood vessels. By driving blood vessel apoptosis VB-111 deprives tumor of blood supply. In Phase 1/2 tiral VB-111 increased patients median overall survival from 5.8 months to 16.6 months. The Phase 3 trial has been initiated, it is expected to recruit 450 patients from 70 clinical sites in the United States and Israel. 

VGX-3100 is also a gene therapy for cervical cancer, as well as for other cancers caused by human papillomavirus. This therapy uses a unique approach to gene delivery, called Cellectra: DNA with a gene of interest, like papilloma virus antigen, is loaded into a proprietary device that sends it into skin by an electric impulse. Inside the skin cells delivered DNA starts producing proteins that alert the immune system to the presence of the virus and associated cancer (18). VGX-3100 has shown promising results for the treatment of cervical dysplasia. It is now in the Phase 3 of clinical trials (19). 

Developing cancer gene therapies is a difficult task. The success depends on the alignment of a working technology, market need, investor’s faith, and the perseverance of researchers. Let’s hope that those alignments will start happening more often.

References

  1. NIH National Cancer Institute. What is Cancer? 
  2. Human Gene Therapy. The First Approved Gene Therapy Product for Cancer Ad-p53 (Gendicine): 12 Years in the Clinic
  3. Financial Times. Cancer drug divides opinion 
  4. Journeyman Pictures. China’s Cancer Drug – China 
  5. Current Cancer Drug Targets. Oncorine, the World First Oncolytic Virus Medicine and its Update in China 
  6. American Cancer Society. Key Statistics for Nasopharyngeal Cancer 
  7. Melanoma Management. Talimogene laherparepvec: overview, combination therapy and current practices 
  8. American Journal of Clinical Dermatology. Talimogene Laherparepvec (T-VEC) and Other Oncolytic Viruses for the Treatment of Melanoma 
  9. International Journal of Oncology. The ‘timely’ development of Rexin-G: First targeted injectable gene vector (Review) 
  10. ClinicalTrials.gov 
  11. Journal of Global Oncology. Survival data following phase 1/2 studies using precision tumor-targeted gene delivery to advanced chemotherapy-resistant malignancies 
  12. ClinicalTrials.gov BLESSED: Expanded Access for DeltaRex-G for Advanced Pancreatic Cancer and Sarcoma 
  13. NIH National Cancer Institute. CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers 
  14. Novartis. Kymriah 
  15. Yescarta 
  16. Advantagene. Prostate Cancer 
  17. Gynecologic Oncology. Ofranergene obadenovec (VB-111) in platinum-resistant ovarian cancer; favorable response rates in a phase I/II study are associated with an immunotherapeutic effect
  18. Inovio. DNA Medicines Technology 
  19.  Inovio. HPV-Associated Diseases