Oncograms Visualize Factors Influencing Long-Term Survival of Cancer Patients Treated with Adenoviral Oncolytic Immunotherapy

Abstract

The first US Food and Drug Administration (FDA)- and EMA-approved oncolytic virus has been available since 2015. However, there are no markers available that would predict benefit for the individual patient. During 2007-2012, we treated 290 patients with advanced chemotherapy-refractory cancers, using 10 different oncolytic adenoviruses. Treatments were given in a Finnish Medicines Agency (FIMEA)-regulated individualized patient treatment program (the Advanced Therapy Access Program [ATAP]), which required long-term follow-up of patients, which is presented here. Focusing on the longest surviving patients, some key clinical and biological features are presented as "oncograms." Some key attributes that could be captured in the oncogram are suggested to predict treatment response and survival after oncolytic adenovirus treatment. The oncogram includes immunological laboratory parameters assessed in peripheral blood (leukocytes, neutrophil-to-lymphocyte ratio, interleukin-8 [IL-8], HMGB1, anti-viral neutralizing antibody status), features of the patient (gender, performance status), tumor features (histological tumor type, tumor load, region of metastases), and oncolytic virus-specific features (arming of the virus). The retrospective approach used here facilitates verification in a prospective controlled trial setting. To our knowledge, the oncogram is the first holistic attempt to identify the patients most likely to benefit from adenoviral oncolytic virotherapy.

Keywords: adenovirus; anti-cancer; cancer; immunogram; immunostimulation; immunotherapy; oncogram; oncoimmunology; oncolytic adenovirus; oncolytic virotherapy.

Figure 1

Survival Graph of ATAP Patients, Including the Best and Worst Surviving Subgroups Survival of all ATAP patients (2), including the subgroups of the best (1) and worst (3) survivors.

Figure 2

Oncograms of the Best Surviving Patients Values at the outer rim indicate good prognostic or predictive variables, while values at the inner rim indicate the opposite. Data that were not available are indicated with data points in between, and the outer rim does not have labeling. Good prognostic variables, as recorded before first oncolytic virus treatment, include: (1) female gender; (2) WHO 0–1; (3) cancers other than melanoma, colorectal, pancreatic, hepatocellular, or cholangiocarcinoma; (4) low tumor load; (5) peritoneal metastases without liver metastases; (6) low neutrophil-to-lymphocyte ratio; (7) low leukocyte value; (8) low IL-8; (9) low HMGB1; (10) first treatments with GM-CSF or CD40L armed virus; and (11) no anti-viral neutralizing antibodies.

Figure 3

Swimmers Plot: Patient-by-Patient Oncolytic Virus Treatments, Responses, and Survival

Figure 4

Average Oncograms: Best and Worst Surviving Patients (A) Average oncograms by tumor type of the best surviving patients (when more than three patients per group were present) compared with the worst surviving controls. (B) Average oncograms of all best surviving patients (n = 30) compared with the worst surviving controls (n = 26). *p < 0.05; **p < 0.01; ***p < 0.001, Fisher’s exact test. When all variables (best survivors: n = 243, worst survivors: n = 174) were compared, p = 0.000002.