A systematic analysis of experimental immunotherapies on tumors differing in size and duration of growth

Abstract

We conducted a systematic analysis to determine the reason for the apparent disparity of success of immunotherapy between clinical and experimental cancers. To do this, we performed a search of PubMed using the keywords "immunotherapy" AND "cancer" for the years of 1980 and 2010. The midspread of experimental tumors used in all the relevant literature published in 2010 were between 0.5-121 mm(3) in volume or had grown for four to eight days. Few studies reported large tumors that could be considered representative of clinical tumors, in terms of size and duration of growth. The predominant effect of cancer immunotherapies was slowed or delayed outgrowth. Regression of tumors larger than 200 mm(3) was observed only after passive antibody or adoptive T cell therapy. The effectiveness of other types of immunotherapy was generally scattered. By comparison, very few publications retrieved by the 1980 search could meet our selection criteria; all of these used tumors smaller than 100 mm(3), and none reported regression. In the entire year of 2010, only 13 used tumors larger than 400 mm(3), and nine of these reported tumor regression. Together, these results indicate that most recent studies, using many diverse approaches, still treat small tumors only to report slowed or delayed growth. Nevertheless, a few recent studies indicate effective therapy against large tumors when using passive antibody or adoptive T cell therapy. For the future, we aspire to witness the increased use of experimental studies treating tumors that model clinical cancers in terms of size and duration of growth.

Figure 1. Precipitous falloff in the number of publications in the year 2010 with increasing size of tumors treated by immunotherapy. A search of PubMed using the keywords “immunotherapy” AND “cancer” recovered 195 experimental studies that met our selection criteria. 75% of tumors treated in these studies were smaller than 121 mm³. Note the sparseness of publications presenting tumors larger than 375 mm³. (n = 195; Q1 = 0.5, Q2 = 45, Q3 = 121.4)

Figure 2. Most experimental tumors are treated less than a week after tumor cell inoculation. The median time reported was five days. All 158 cancer immunotherapy studies listed in PubMed meeting our selection criteria for 2010 using syngeneic murine tumor models are presented. Only nine tumors have grown for 14 d or longer before treatment. (n = 158; Q1 = 4, Q2 = 5, Q3 = 8)

Figure 3. Most experimental immunotherapies published treat small tumors yet succeed only at slowing or delaying tumor growth, but in several recent reports, larger tumors are being treated and a few reports present tumor regression. An effect size (E) of 1 indicates the treatment arrested tumor growth. An E < 1 indicates that the treated tumor still grew progressively, but only slower than the control or in a delayed fashion, i.e., a reduction of the growth rate of the tumor. An E > 1 indicates tumor regression. (Left panel) Detailed analysis was done for all experimental cancer immunotherapy publications listed in PubMed for April, June, and November of 2010. Regression of tumors larger than 200 mm³ is observed only after passive antibody or adoptive T cell therapy. (n = 74). (Right panel) The same analysis was performed for those publications in the entire year of 1980. Very few publications presented analyzable data. No publication uses tumors larger than 200 mm³, and regression is not observed at all. (n = 10).