Monoclonal Antibodies and Nonspecific Immunotherapy

00:01 There are a number of ways of harnessing the immune system to attack tumors - non-specific immunotherapy, the use of other types of monoclonal antibodies, cell transfer, gene therapy and vaccines.

00:25 Looking at non-specific immunotherapy, there are a number of agents that are very beneficial in the treatment of tumors. Interferon-α is used in the treatment of AIDS-related Kaposi sarcoma, hairy cell leukemia, chronic myelogenous leukemia and melanoma.

00:46 Interleukin-2 has utility in the treatment of renal cell carcinoma and melanomas.

00:53 And BCG can be used in the treatment of melanoma, superficial bladder carcinoma, acute myeloblastic leukemia, ovarian carcinoma and Non-Hodgkin lymphoma.

01:07 Here are some examples of monoclonal antibodies used for the treatment of cancer.

01:14 I’m not going to read through this whole list.

01:17 You can see yourself that these various monoclonal antibodies can target molecules such as VEGF, RANKL, GD2, CTLA-4, PD-1 and so forth.

01:29 We’ve already mentioned PD-1.

01:31 So as you can see, there are a variety of different monoclonal antibodies that are available targeting a number of different molecules.

01:39 And these have been approved by the FDA for use in a variety of different tumors.

01:45 As well as using antibodies on their own to fight tumors, for example by blocking the interaction between PD-1 and PD-L1.

01:54 One can use monoclonals to deliver a toxic molecule to the tumor.

02:01 And we have three examples here.

02:04 Brentuximab vedotin is a monoclonal antibody that is targeted to CD30 which is present on the surface of a number of tumor cells.

02:16 And this antibody is conjugated to monomethyl auristatin E, which is an antimitotic agent.

02:24 So the antibody delivers specifically to the tumor because the tumor cell has this molecule CD30 on its cell surface.

02:33 The antibody acts to target the antimitotic agent to the tumor cell.

02:40 This has been approved for use in Hodgkin lymphoma and in anaplastic large cell lymphoma.

02:47 Ibritumomab tiuxetan targets CD20.

02:54 In this case the monoclonal antibody is coupled with a radioactive isotope, yttrium90.

03:02 This is approved for use in B-cell non-Hodgkin lymphoma.

03:06 Denileukin diftitox targets CD25.

03:11 CD25 is the α-chain of the interleukin-2 receptor.

03:15 And this particular agent is a combination of interleukin-2 which will bind to its receptor CD25 with diphtheria toxin.

03:26 This is approved for use in cutaneous T-cell lymphoma.

03:30 Normally the two antigen binding arms of an antibody molecule are absolutely identical to each other.

03:36 They bind exactly the same antigen.

03:38 However in the laboratory, you can create an artificial antibody where one arm has specificity for one antigen and the other arm has specificity for a different antigen.

03:50 And here we can see on normal healthy cells, one cell type has one particular antigen and another cell type has a different type of antigen.

04:01 However on some tumor cells, both antigens will be expressed.

04:05 And it’s only on the tumor cell that both of these antigens are expressed.

04:09 On normal cells they’ll either have one antigen or they’ll have the other but not both.

04:14 This characteristic of tumor cells can be capitalized upon by using bispecific monoclonal antibodies that bind to both of these molecules, and therefore will bind more strongly to the tumor cells using this synergistic binding.

04:31 An alternative approach using bispecific antibodies is to have one arm of the antibody specific for a tumor antigen, and the other arm specific for something like CD8 that’s present on a cytotoxic T-cell, enforcing an interaction between the cytotoxic cell and the tumor cell.

04:52 Adoptive cell transfer is a term used for the transfer of lymphocytes into a patient.

05:00 So here we have a tumor bearing patient, and one can isolate lymphocytes from either the blood of this patient or from the lymphocytes that are infiltrating the tumor.

05:14 Having taken these tumor specific lymphocytes out of the patient, one can expand these in culture, using cytokines such as interleukin-2.

05:27 So maybe the patient is making an immune response to the tumor but it’s inadequate.

05:32 There simply aren’t enough anti-tumor cells there to do the jobs that-- job that’s needed.

05:37 So take the cells out and grow them up, so you have a much greater number.

05:43 You could also transfect these cells.

05:46 For example, with a CAR gene.

05:49 Now CAR stands for chimeric antigen receptor.

05:55 And these chimeric antigen receptors can be generated so that they will recognize tumor antigens.

06:03 For example, here we have a antibody based chimeric antigen receptor with the Variable region from the heavy chain of an antibody, and the Variable chain of-- the Variable region of the light chain linked together into what is called a single chain Fb, and that is recognizing a tumor antigen.

06:25 This chimeric antigen receptor can have ITAMs linked to it and other desirable sequences linked to help in causing death of the tumor cell.

06:39 So expanding up these tumor infiltrating lymphocytes or lymphocytes in the peripheral blood, perhaps transfecting them with a CAR.

06:47 And then transferring those cells back into the patient can help the immune system, give it a helping hand if you like, by expanding up the number of cells and modifying them in various ways, can help these T-cells to cause tumor regression.