Oncology Insights — Cell and Gene Therapy: Changing the Cancer Paradigm

December 15, 2023

Developments in cell and gene therapy have led to remarkable advancements in cancer drug therapy.

Cell and Gene Therapy: Changing the Cancer Paradigm

Developments in cell and gene therapy have led to remarkable advancements in cancer drug therapy. At times, it is unclear if an agent is a cell or gene therapy or both. FDA approved cell and gene therapy include cell therapy, patient derived cellular gene therapy and viral vectors, with plasmid DNA and human gene editing therapies moving through the pipeline.

Based on the FDA Center for Biologics Evaluation and Research (CBER), cell therapy products include cellular immunotherapies, cancer vaccines, and other autologous and allogeneic cells used for certain therapeutic indications.¹ The FDA has approved 2 cancer vaccines which are first in their class. Provenge® (sipuleucel-T) is a therapeutic vaccine manufactured usingx ex vivo gene therapy and is indicated for the treatment of advanced hormone-refractory prostate cancer patients.2,3 Imlygic™ (talimogene laherparepvec) is an oncolytic virus immunotherapy for management of late-stage melanoma patients.

Human gene therapy is a technique that may adjust or change the expression of a gene or modify the biological properties of living cells to treat or cure a condition.4-5 In oncology, current treatment options include patient-derived cellular gene therapy and viral vectors used to carry genes into human cells.³

Patient derived cellular gene therapy includes adoptive cellular therapy like chimeric antigen receptor T-cell (CAR T) and tumor-infiltrating lymphocyte (TIL).6-12 For both immune-oncology drug classes, T-cells are replicated and infused back into the patient to kill cancer cells. There are some notable differences between these 2 drug classes.

For CAR T therapy, after the patient’s T-cells are collected and transported to the lab, depending on the agent, a retrovirus or lentivirus carries the transgene (which is DNA encoding for a chimeric antigen receptor (CAR)) into the T-cell. The CAR is replicated and the identified antigen (ex. CD19, BCMA, etc.) is expressed on the T-cell surface. These re-engineered T-cells now have specificity to bind and target cells that carry the identified antigen.13-15

TIL therapy is not FDA approved. Lifileucel, in combination with Keytruda (pembrolizumab), is a one-time TIL therapy currently under FDA review as a second line treatment option for patients with advanced melanoma.16-19 With TIL therapy, CD8-positive T-cells, also known as tumor-infiltrating lymphocytes, are found in the tumor, identified, and replicated. These lymphocytes, because they have demonstrated the ability to recognize and infiltrate the cancer, have enhanced tumor targeting potential.¹³

Viral vector products that use modified viruses, such as lentivirus, to deliver therapeutic genes into human cells has also received FDA approval.4 Adstiladrin® (nadofaragene firadenovec-vncg) is a viral vector, intravesical product for the treatment of patients with high-risk BCG-unresponsive non-muscle invasive bladder cancer.20

In the near future, medications that employ human gene editing technology that alter the gene with the purpose of disrupting the harmful genes or repairing mutated ones and plasmid DNA which utilize circular DNA to deliver therapeutic genes into the human cells may be approved as options for cancer therapy.4,22,23

On November 28, 2023, it was announced that due to reports of T-cell malignancies, including chimeric antigen receptor CAR-positive lymphoma, the FDA has initiated a probe into the risk of secondary cancer following CAR T therapy for all approved agents.25 Because of the known potential of developing secondary malignancies from gene therapy products that utilize lentiviral or retroviral vectors, the initial FDA approvals included a 15-year observational safety studies to assess the long-term safety and the risk of secondary malignancies occurring after treatment. In addition, patients who received treatment during clinical trials, should undergo life-long monitoring for new malignancies.  

As evaluation of the long-term impact of gene therapy continues, new drug classes are moving through the pipeline. Newly approved cellular gene therapy products are expected to be priced in the same range as CAR T therapy. However, the price of gene editing and plasmid DNA therapy is unknown. If the current trends observed with new to market drugs in cancer treatment continues, the price of newly approved agents will likely be high and push current boundaries.  

FDA Approved Gene Therapy (includes upcoming FDA reviews for indication expansion) 

Category Initial Approval Date Brand Name Generic Name Indication(s) Target Number of Doses Annual WAC FDA Review Date of Expanded Indication Potential Indication Expansion
Cell Therapy (Cancer Vaccines) Apr-10 Provenge® sipulevel-T Metastic castration-resistant prostate cancer (mCRPC) Prostatic acid phosphatase (PAP) 3 (∼2 wks interval) $187,808 N/A N/A
Cell Therapy (Cancer Vaccines) Nov-15 IMLYGIC® talimongene laherparepvec Metastatic melanoma N/A First 2 (∼3 wks interval), then q2w if injectable tumors available $633,631 N/A N/A
Cellular Gene Therapy (CAR T) Mar-21 Abecma®

Idecabtagene**

vicleucel (ide-cel)

R/R MM BCMA 1 $498,408 Dec-16-2023 Third line for R/R MM after two to four prior lines of treatment
Cellular Gene Therapy (CAR T) Feb-21 Breyanzi®

lisocabtagene**

maraleucel (liso-cel)

RR LBCL 2L, RR LBCL after 2 or more lines CD19 1 $487,477 Mar-14-2024 Third line in CLL and SLL
Cellular Gene Therapy (CAR T) Feb-22 Carvykti® Ciltacabtagene** autoleucel (cilta-cel) R/R MM BCMA 1 $478,950 Q2-2024 Second line for R/R MM after lenalidomide failure
Cellular Gene Therapy (CAR T) Aug-17 Kymriah® tisagenlecleucel** (tisa-cel) RR pediatric/young adult ALL, RR DLBCL, RR FL CD19 1 $427,048 N/A N/A
Cellular Gene Therapy (CAR T) Oct-17 Yescarta®

axicabtagene**

(Ciloleucel (axi-cel)

R/R large B-cell lymphoma, R/R LBCL with failure w/in 12 months; R/R FL CD19 1 $462,000 N/A N/A
Cellular Gene Therapy (CAR T) Jul-20 Tecartus®

brexucabtagene**

autolecel (brexucel)

RR MCL, RR B-cell ALL CD19 1 $424,000 N/A N/A
Viral Vector Dec-22 Adstiladrin®

nadofaragene firadenovec-vncg

High-risk BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) Human interferon alfa-2b (IFNa2b) 4 $164,337 N/A N/A

Gene Therapy Pipeline

Category Pipeline Drug Name Route Gene Therapy Type Indication Stage FDA Review Date
Cellular Gene Therapy (Til Therapy)

Lifileucel

(TBD)

Intravenous Autologous tumor-infiltrating lymphocyte Advanced melanoma (progression past anti-PD-1/L1 therapy) Phase II 24-Feb-24
Plasmid and Viral Vectors Adstiladrin (Nadofaragene firadenovec) Intravesical Viral Vector Mesothelioma Pase III N/A
Plasmid and Viral Vectors GEN-1

(TBD)

Injectable Plasmid DNA Peritoneal cancer Ovarion Cancer Phase II Phase II N/A
Plasmid and Viral Vectors Reqorsa (Quaratus ugene ozeplasmid) Intravenous Plasmid DNA Non-small cell lung cancer (NSCLC) Phase II N/A
Plasmid and Viral Vectors pIL-12 (Tavokinogene telseplasmid) Intratumor injection Plasmid DNA Breast cancer Malignant melanoma Phase II Phase II N/A
Cellular Immunotherapy and Gene Therapy Ad-RTS-hIL012 (TBD) Intratum or injection Cellular Immunotherapy Gene Therapy Melanoma Breast cancer Phase II Phase II N/A
Gene Editing NeoTCR-P1 (TBD) Injectable Cellular gene therapy; Edited PD-1 on T cells Solid tumors Phase I N/A
References
  1. Cellular & Gene Therapy Products. Available at https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products#:~:text=Cellular%20therapy%20products%20include%20cellular,adult%20and%20embryonic%20stem%20cells. Accessed November 20, 2023.
  2. Provenge [package inset]. Seattle, WA; Dendreon; July 2017.
  3. Grozescu T, Popa F. Immunotherapy and gene therapy in prostate cancer treatment. J Med Life. 2017 Jan-Mar;10(1):54-55. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304374/ .
  4. What is gene Available at https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-therapy#footnote1. Accessed November 17, 2023.
  5. How does gene therapy work? Available at https://medlineplus.gov/genetics/understanding/therapy/procedures/ . Accessed November 17, 2023.
  6. Yescarta [package insert]. Santa Monica, CA; Kite Pharma, Inc.; April 2022.
  7. Kymriah [package insert]. East Hanover, New Jersey; Novartis; May 2022.
  8. Breyanzi [package insert]. Summit, NJ; BMS; June 2023.
  9. Tecartus [package insert]. Santa Monica, CA; Kite Pharma; October 2021.
  10. Abecma [package insert]. Summit, NJ; Celgene; March 2021.
  11. Carvykti [package inset]. Somerset, NJ; Janssen; February 2023.
  12. Granhøj JS, Witness Præst Jensen A, Presti M, Met Ö, Svane IM, Donia M. Tumor-infiltrating lymphocytes for adoptive cell therapy: recent advances, challenges, and future directions. Expert Opin Biol Ther. 2022 May;22(5):627-641. doi: 10.1080/14712598.2022.2064711. 
  13. Jayaraman J, Mellody MP, Hou AJ, et al. CAR-T design: Elements and their synergistic function. EBioMedicine. 2020 Aug;58:102931. doi: 10.1016/j.ebiom.2020.102931.
  14. Firor AE, Jares A, Ma Y. From humble beginnings to success in the clinic: Chimeric antigen receptor-modified T-cells and implications for immunotherapy. Exp Biol Med (Maywood). 2015 Aug;240(8):1087-98. doi: 10.1177/1535370215584936. Journal of Clinical Oncology 2023 41:16_suppl, TPS9607
  15. Ataca P, Arslan Ö. Chimeric Antigen Receptor T Cell Therapy in Hematology. Turk J Haematol. 2015 Dec;32(4):285-94. doi: 10.4274/tjh.2015.0049.
  16. T-cell transfer Therapy. Available at https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/t-cell-transfer-therapy. Accessed 11-20-23.
  17. Zhao Y, Deng J, Rao S, et al. Tumor Infiltrating Lymphocyte (TIL) Therapy for Solid Tumor Treatment: Progressions and Challenges. Cancers (Basel). 2022 Aug 27;14(17):4160. doi: 10.3390/cancers14174160. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9455018/ 
  18. A phase 3 study (TILVANCE-301) to assess the efficacy and safety of lifileucel, an autologous tumor-infiltrating lymphocyte cell therapy, in combination with pembrolizumab compared with pembrolizumab alone in patients with untreated unresectable or metastatic melanoma.Olson D, Hong Y, Thomas SS, et al. Journal of Clinical Oncology 2023 41:16_suppl, TPS9607. Available at https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.TPS9607  
  19. Ryan C. FDA Extends Priority Review of BLA for Lifileucel in Advanced Melanoma. Available at https://www.onclive.com/view/fda-extends-priority-review-of-bla-for-lifileucel-in-advanced-melanoma . Accessed November 20, 2023.
  20. Adstiladrin [package inset]. Kuopio, Kastrup, Denmark; Ferring; September 2023.
  21. Genetic Therapies: Benefits and Risks. Available at https://www.nhlbi.nih.gov/health/genetic-therapies/benefits-risks#:~:text=Genetic%20therapies%20hold%20promise%20to,if%20an%20injection%20is%20involved. Accessed November 17, 2023.
  22. Stefanoudakis D, Kathuria-Prakash N, Sun AW, et al. The Potential Revolution of Cancer Treatment with CRISPR Technology. Cancers (Basel). 2023 Mar 17;15(6):1813. doi: 10.3390/cancers15061813. 
  23. National Library of Medicine. https://clinicaltrials.gov/ . Accessed Dec 10, 2023,
  24. IPD Analytics. November 21, 2023
  25. FDA Investigating Serious Risk of T-cell Malignancy Following BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T cell Immunotherapies. Available at https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous. Access December 9, 2023.

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