Intratumoral History

HISTORY OF INTRATUMORAL IMMUNOTHERAPY

overview

The first evidence of successful intratumoral immunotherapy was reported at the end of the 19th century following intratumoral injections of pro-inflammatory bacterial extracts. As new immune system components such as interferon, T cells, dendritic cells and NK cells were discovered, the immune system became better understood which forged a path for the development of new drugs.

There were not many immunotherapeutic drugs available until monoclonal antibodies and BCG (Bacillus Calmette–Guérin) were developed in the 1970s. Over the past 50 years there have been a small number of clinical studies that involved intratumoral immunotherapy, with varying degrees of success. Essentially, physicians studied intratumoral therapy using the latest drugs that were available to them.

More recently, there has been a resurgence of interest in intratumoral cancer immunotherapy with the success and availability of systemic immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4, as well as numerous other antagonists, agonists, cytokines, and adjuvants.  However, all of these drugs are formulated for systemic administration and are suboptimal for intratumoral injection, which presents challenges when administered within the tumor.  

In addition, there have been anecdotal reports of an “abscopal effect” following the ablation (oncolysis) of solid tumors with modalities such as radiation, radiofrequency ablation and cryotherapy.  This was first observed in 1953 when the irradiation of a primary tumor resulted in the clearance of distant, non-radiated tumors. Although extremely rare, it shows that systemic anti-tumor responses could result from local treatment.

Since its discovery, achieving an abscopal effect has been highly sought after, as it is the best hope for curing patients with metastatic cancer.  The Syncrovax™ therapy aims to elicit abscopal effects to potentially eradicate metastatic cancers. To attain this, Syncromune™ has devised a novel therapy that focuses on harnessing both oncolysis and intratumoral multi-medicine drug delivery.

We believe that the combination of oncolysis and intratumoral immunotherapy could elicit abscopal effects and be the key to empowering each patient’s immune system to identify, attack and potentially eradicate cancer throughout the body. The Syncromune™ clinical development program focuses on optimizing and advancing multi-medicine intratumoral immunotherapy to target metastatic solid tumors.

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2020

first intratumoral immunotherapy
Coley reported the first evidence of successful cancer intratumoral immunotherapy at the end of the 19th century involving intratumoral injections of pro-inflammatory bacterial extracts.
A
1893
Abscopal effect first described
Mole reported the first evidence of an abscopal effect after local radiation of tumor-bearing animals resulted in clearance of distant, non-radiated tumors.
1953
intratumoral c. parvum
Likhite & Halpern demonstrated that intratumoral injection of C. parvum prevented progressive growth breast cancer visceral metastases in rats.
1974
intratumoral autologous lymphocytes
Young reported intratumoral injection of autologous leukocytes (lymphocyte-monocytes) directly into glioblastoma.
1977
intratumoral BCG
McLaughlin demonstrated the efficacy of intratumoral immunotherapy with BCG
1978
intratumoral combination r-TNF + r-IL-2
Nishimura reported use of an intratumoral combination therapy with r-TNF and recombinant human interleukin-2 (r-IL-2) in mice demonstrated inhibition of tumor regrowth.
1987
combination cryotherapy + intratumoral BCG
Iavorskiĭ first reported the use of combination cryotherapy plus intratumoral injection of the BCG vaccine
1987
herpes simplex virus + intratumoral IL-12
Toda first reported the use of intratumoral inoculation of replication-competent, attenuated herpes simplex virus followed by intratumoral injection of IL-12.
1998
radiotherapy + intratumoral dendritic cells
Teitz-Tennenbaum reported that intratumoral dendritic cell administration combined with radiotherapy induced a potent local and systemic antitumor response in tumor-bearing mice.
2003
cryoablation + intratumoral dendritic cells
Machlenkin was the first to report systemic antimetastatic immunity after using cryotherapy of tumors combined with subsequent in situ immunotherapy with autologous unmodified immature dendritic cells.
2005
cryoablation + intratumoral interleukins
Williams reported use of cryoablation combined with intratumoral interleukins or interferon for solid tumors and bone tumors.
2012
cryoablation + intratumoral anti-CTLA-4 and anti-PD-1
Williams reported the first human use of cryoablation combined with intratumoral anti-PD-1 and anti-CTLA-4.
2014
combined intratumoral oncolytic virus + GM-CSF
T-VEC becomes the first FDA approved intratumoral oncolytic immunotherapy, which utilizes a genetically engineered herpes virus that expresses human GM-CSF.
2015
cryosurgical lysis + intratumoral anti-CTLA-4, anti-PD-1 & GM-CSF
Onik presented the use of in situ cryosurgical lysis followed by intratumoral injection of anti-PD-1, anti-CTLA-4 and GM-CSF for the treatment of metastatic prostate cancer. Reported 50% complete response rate.
2020
references
  1. Coley WB. The treatment of malignant tumors by repeated iniculations of erysipelas: with a report of 10 original case. Am J Med 1893; 105: 487–510.

  2. Mole, R. H. (1953). “Whole body irradiation; radiobiology or medicine?” Br J Radiol 26(305): 234-241.

  3. Likhite, V. V., Halpern, B. N. (1974) Lasting rejection of mammary adenocarcinoma cell tumors in DBA-2 mice with intratumor injection of killed Corynebacterium parvum. Cancer Res. 34: 341- 344

  4. McLaughlin, C. A., Cantrell, J. L., Ribi, E., Goldberg, E. P. (1978) Intratumor chemoimmunotherapy with mitomycin C and components from mycobacteria in regression of line-10 tumors in guinea pigs. Cancer Res. 38: 1311± 1316

  5. Young H., et al. Immunotherapy with autologous white cell infusions (“lymphocytes”) in the treatment of recurrent glioblastoma multiforme: a preliminary report. Cancer. 1977 Sep;40(3):1037-44.

  6. Nishimura T., et al. Combination tumor-immunotherapy with recombinant tumor necrosis factor and recombinant interleukin 2 in mice. Int J Cancer. 1987 Aug 15;40(2):255-61.

  7. Iavorskiĭ V., et al. Combined treatment of patients with metastases of skin melanoma using cryotherapy. Vopr Onkol. 1988;34(7):799-803.

  8. Toda M., et al. In Situ Cancer Vaccination: An IL-12 Defective Vector/Replication-Competent Herpes Simplex Virus Combination Induces Local and Systemic Antitumor Activity. J Immunol. 1998 May 1;160(9):4457-64.

  9. Teitz-Tennenbaum S., et al. Radiotherapy potentiates the therapeutic efficacy of intratumoral dendritic cell administration. CANCER RESEARCH 63, 8466–8475, December 1, 2003

  10. Machlenkin A., et al. Combined Dendritic Cell Cryotherapy of Tumor Induces Systemic Antimetastatic Immunity. Clin Cancer Res 2005;11(13) July 1, 2005.

  11. American Cancer Ablation Center Working with New ‘Tumor Vaccine’ to Boost Body’s Natural Ability to Fight Untreated Cancerous Tumors. American Cancer Ablation Center, 12 July 2012. https://www.prnewswire.com/news-releases/american-cancer-ablation-center-working-with-new-tumor-vaccine-to-boost-bodys-natural-ability-to-fight-untreated-cancerous-tumors-162042425.html. Press release, PDF download.

  12. Cryoablation Combined With Intra-tumoral Injection of Immunotherapeutic Drugs Offers Promising Outcomes. Immuno-oncology News, 10 February 2015. https://immuno-oncologynews.com/2015/02/10/cryoablation-combined-with-intra-tumoral-injection-of-immunotherapeutic-drugs-offers-promising-outcomes/. 

  13. Pol J., et al. First oncolytic virus approved for melanoma immunotherapy. ONCOIMMUNOLOGY 2016, VOL. 5, NO. 1, e1115641
  14. Rosenberg M., Williams J. Image guided cryoablation of cancer with intratumoral injection of anti-CTLA-4 and PD-1 immune check-point inhibitors. Journal for Immunotherapy of Cancer 2015, 3(Suppl 2):P142

  15. Onik G., et al. Abstract 6540: Regression of metastatic cancer and abscopal effects following in situ vaccination by cryosurgical tumor cell lysis and intratumoral immunotherapy: A case series. Presented at AACR Virtual Annual Meeting II 2020; June 22-24, 2020.