Adoptive Cell Therapy—Act 1: The Beginning

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Frederick R. Appelbaum, MD

Frederick R. Appelbaum, MD

ON AUGUST 30, 2017, the first genetically engineered T-cell therapy (tisagenlecleucel [Kymriah]) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse. This approval is a climactic moment in the latest scene of what is turning into an award-winning play: the development of adoptive cell therapy. Where and when did this play begin? 

Taking a very broad view, one could go back more than a century to the oft-told story of William Coley, who, based on observations of rare tumor regression in patients who developed postoperative infections, created a mixture of heat-killed bacteria for intratumoral injections, leading to occasional tumor responses.1

Dr. Appelbaum is Executive Vice President and Deputy Director, External Affairs, Fred Hutchinson Cancer Research Center, Seattle.

But Dr. Coley’s efforts relate to cancer immunotherapy generally, and not to adoptive cell therapy specifically. 

A more appropriate opening scene for adoptive cell therapy might involve Barnes and Loutit in the mid-1950s working at the Medical Research Council Radiobiological Research Unit in Harwell, Berkshire, a village about 13 miles south of Oxford and the site of Europe’s first nuclear reactor. Several years earlier, Jacobson et al had published their famous experiment showing that mice given otherwise lethal doses of total-body irradiation recovered if their spleens were shielded by lead, but the mechanism underlying this effect was uncertain.2 

The first act of adoptive cell therapy began with the appreciation of the graft-vs-tumor effect.
— Frederick R. Appelbaum, MD

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In 1955, Ford, Hamerton, Barnes, and Loutit definitively demonstrated the cellular basis of this protective effect when they showed that the intravenous infusion of isologous (syngeneic) bone marrow cells could overcome otherwise lethal total-body irradiation.3 Reasoning that if total-body irradiation could destroy a normal marrow, it might be used therapeutically to destroy an abnormal one, they began to explore the effects of total-body irradiation and subsequent marrow infusion in mice inoculated with a radiation-induced leukemia cell line (151/1). 

Destroying Cancer Cells by Immune Reaction 

IN 1957, they published the results that really start our play.4 They found that almost all leukemia-bearing mice given total-body irradiation followed by isologous bone marrow died of leukemia progression within 1 month of treatment. In contrast, animals given homologous (allogeneic) marrow lived, on average, twice as long posttransplant before dying free of leukemia but with a “wasting syndrome,” which we now know to be graft-vs-host disease. The authors concluded the homologous graft “might be able to produce an immune reaction to destroy any surviving leukemia cells.” 

At the time of the Barnes and Loutit publication, the concept that tumors could be the target of an immune response was already established. For example, several years earlier (1953), Foley demonstrated that methylcholanthrene-induced tumors were antigenic in isologous mice by showing hosts were resistant to a second inoculation after an initial tumor was destroyed by ligation.5 But until the work of Barnes and Loutit, it had never been demonstrated that tumors could be eradicated by the transfer of cells. Of course, the antigenic targets in the case of Barnes and Loutit were not tumor-specific but rather histocompatibility antigens. 

Over the ensuing several years, a large number of studies were performed exploring the variable antigenicity of murine tumors and methods to prevent their outgrowth or transfer.6 These studies demonstrated both humoral and cellular contributions to antitumor immunity, but until the early 1970s, efforts to eliminate established tumors by adoptive transfer of isologous (rather than allogeneic) immune cells and/or sera were universally unsuccessful. 

Then, in 1972, Fass and Fefer of the Seattle transplant team published results showing that mice inoculated with Friend-lymphoma cells (FBL3) could be cured if treated with cyclophosphamide plus infusion of viable spleen cells from mice preimmunized against FBL3.7 This was the first report of a therapy conceptually analogous to the chimeric antigen receptor (CAR) T-cell therapies that are the current stars in our play. 

Expanding Knowledge About Immunotherapy 

IN THE EARLY 1970S, knowledge about immunotherapy of murine tumors rapidly expanded, but there was scant evidence of its relevance to human disease until later in that decade. Then, in observations very similar to those of Barnes and Loutit in mice, the Seattle team published their results from human studies showing that relapse rates following allogeneic transplantation were markedly lower in patients who developed graft-vs-host disease compared with those who did not.8 Additional observations showed that relapse rates were lowest in those who developed both acute and chronic graft-vs-host disease, somewhat higher in those who had no clinical evidence of graft-vs-host disease, and higher yet if T cells were removed from the marrow inoculum in an effort to prevent graft-vs-host disease and in recipients of syngeneic marrow.9,10 

By the mid-1980s, it was generally accepted that adoptive transfer of allogeneic T cells could be of benefit, but was of limited potency….
— Frederick R. Appelbaum, MD

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Further verification of a graft-vs-tumor effect came from efforts to treat patients for posttransplant leukemic recurrence by infusing viable donor lymphocytes, resulting in sustained complete remissions in most patients with chronic myelogenous leukemia and in some patients with other hematologic malignancies.11 By the mid-1980s, it was generally accepted that adoptive transfer of allogeneic T cells could be of benefit, but was of limited potency, sometimes associated with significant toxicity in the form of graft-vs-host disease and restricted in its application to the post–allogeneic transplant setting.12 

To make adoptive cell therapy more effective and broadly applicable, a large number of challenges presented themselves, including the requirement to be able to clone and expand tumor-reactive T cells, to define conditions that allow for their expansion and survival after reinfusion, to identify appropriate tumor-associated targets, and to develop methods to genetically engineer T cells to optimize their antitumor efficacy. Over the past several decades, as outlined in many excellent reviews, a number of these challenges have been met, at least for the treatment of CD19-positive tumors.13,14 These advances now set the stage for exploration of adoptive cell therapy in multiple therapeutic settings. 

Still More to Learn 

THE PURPOSE of this brief commentary is not to review the field of adoptive cell therapy, but rather to recall the origins of the story. Adoptive cell therapy began with the observation of a graft-vs-tumor effect, and some of us would argue there is still much to learn by studying the graft-vs-tumor effect in humans. Most obviously, among patients with seemingly similar forms and extent of leukemia undergoing allogeneic transplantation, some will relapse despite developing extensive graft-vs-host disease, whereas others will not, even in the absence of clinical graft-vs-host disease. 

How can these divergent outcomes be explained? Are there identifiable differences in tumor resistance mechanisms? While we understand some of the reasons for resistance to chemotherapeutics, less is known about cell-intrinsic and cell-extrinsic context-dependent resistance to graft-vs-tumor effects. Almost all recurrences occur in the bone marrow. Are there measurable differences in the marrow microenvironment that influence the graft-vs-tumor effect? Further, our knowledge of the reconstitution of donor-derived antitumor immunity in the posttransplant setting is still limited. 

The first act of adoptive cell therapy began with the appreciation of the graft-vs-tumor effect. A number of new investigative tools are now available, which should allow for a deeper description of leukemic cells pre- and posttransplant and a much more complete understanding of immune reconstitution in the blood and bone marrow of patients during the posttransplant period. We can hope that with this knowledge, adoptive cell therapy’s next act will be equally as productive as the last. ■

DISCLOSURE: Dr. Appelbaum reported no conflicts of interest. 


1. Coley WB: The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc R Soc Med 3:1-48, 1910

2. Jacobson LO, Marks EK, Robson MJ, et al: Effect of spleen protection on mortality following x-irradiation. J Lab Clin Med 34:1538-1543, 1949. 

3. Ford CE, Hamerton JL, Barnes DW, et al: Cytological identification of radiation-chimaeras. Nature 177:452-454, 1956

4. Barnes DW, Loutit JF: Treatment of murine leukaemia with x-rays and homologous bone marrow: II. Br J Haematol 3:241-252, 1957

5. Foley EJ: Antigenic properties of methylcholanthrene-induced tumors in mice of the strain of origin. Cancer Res 13:835-837, 1953

6. Klein G: Tumor-specific transplantation antigens: G. H. A. Clowes memorial lecture. Cancer Res 28:625-635, 1968

7. Fass L, Fefer A: Studies of adoptive chemoimmunotherapy of a Friend virus-induced lymphoma. Cancer Res 32:997-1001, 1972

8. Weiden PL, Flournoy N, Thomas ED, et al: Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 300:1068-1073, 1979

9. Weiden PL, Sullivan KM, Flournoy N, et al: Antileukemic effect of chronic graft-versus-host disease: Contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 304:1529-1533, 1981

10. Horowitz MM, Gale RP, Sondel PM, et al: Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75:555-562, 1990

11. Kolb HJ, Schattenberg A, Goldman JM, et al: Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 86:2041-2050, 1995

12. Appelbaum FR: Haematopoietic cell transplantation as immunotherapy. Nature 411:385-389, 2001

13. Rosenberg SA, Restifo NP: Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348:62-68, 2015

14. June CH, Riddell SR, Schumacher TN: Adoptive cellular therapy: A race to the finish line. Sci Transl Med 7:280ps7, 2015.