On 2014 Nov 13, Madhusudana Girija Sanal commented:

The paper from Rosenberg's group titled 'Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer' (1) raises a lot of questions.

• The exact tumor volumes observed in the single patient mentioned in this report are not provided in this paper. Tumor volume details in lungs, liver and other places. This is very important because the entire success story is built on tumor volumes of the lungs and liver.

• Usually more than one T-cell is involved in killing a cancer cell. Even if we assume one T-cell is involved in killing one cancer cell, the amount of cells infused into the patient is not sufficient for the clearance of the tumor mass which should be large (from the description it is clear that the patient is in the advanced stage of her disease).

• Solid tumors are not well perfused and it is not clear how the T-cells managed to get into the solid nodules in sufficient numbers to cause a very significant reduction in tumor volume.

• Solid tumors also suffer from hypoxia. It is well known that hypoxia can impair anti-cancer immunity by altering the function of innate and adaptive immune cells (for example by inhibition of proliferation and induction of cell death) and/or by increasing the intrinsic resistance of tumor cells to the cytolytic activity of immune effectors.

• The mutant protein (note that there is only one amino acid difference) is degraded and processed like any other protein to be displayed on the cancer cell surface by the class one MHC complex. What is the probability that the right epitope of the mutated protein is displayed on a significant proportion of cancer cells to attract immune mediated destruction of the whole cell? Is there any evidence that the mutated protein is over-expressed in this cancer?

• In many cancers class one MHC is down-regulated as a mechanism to evade immunity. Is the scenario very different in this patient?

• If the transfused cells are clearing the tumor cells by recruiting other cells, why didn’t the authors study the changes in the number, distribution and re-activity and cytokine responses of other members of the leukocytes-at least by FACS analysis of circulating immune cells-an easy to do experiment?

• Cancer is a very dynamic process which involves continuous evolution and natural selection. There exists high tumor variability- (cellular, genetic, epigenetic and immunological)-especially in advanced disease-such as a relapse after a few courses of radiotherapy and chemotherapy. How can an immune mediated killing overcome such heterogeneity (of epitopes evolved)?

Reference

1) Tran E et al. Science. 2014 May 9;344(6184):641-5.

On 2014 Nov 13, Madhusudana Girija Sanal commented:

The paper from Rosenberg's group titled 'Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer' (1) raises a lot of questions.

• The exact tumor volumes observed in the single patient mentioned in this report are not provided in this paper. Tumor volume details in lungs, liver and other places. This is very important because the entire success story is built on tumor volumes of the lungs and liver.

• Usually more than one T-cell is involved in killing a cancer cell. Even if we assume one T-cell is involved in killing one cancer cell, the amount of cells infused into the patient is not sufficient for the clearance of the tumor mass which should be large (from the description it is clear that the patient is in the advanced stage of her disease).

• Solid tumors are not well perfused and it is not clear how the T-cells managed to get into the solid nodules in sufficient numbers to cause a very significant reduction in tumor volume.

• Solid tumors also suffer from hypoxia. It is well known that hypoxia can impair anti-cancer immunity by altering the function of innate and adaptive immune cells (for example by inhibition of proliferation and induction of cell death) and/or by increasing the intrinsic resistance of tumor cells to the cytolytic activity of immune effectors.

• The mutant protein (note that there is only one amino acid difference) is degraded and processed like any other protein to be displayed on the cancer cell surface by the class one MHC complex. What is the probability that the right epitope of the mutated protein is displayed on a significant proportion of cancer cells to attract immune mediated destruction of the whole cell? Is there any evidence that the mutated protein is over-expressed in this cancer?

• In many cancers class one MHC is down-regulated as a mechanism to evade immunity. Is the scenario very different in this patient?

• If the transfused cells are clearing the tumor cells by recruiting other cells, why didn’t the authors study the changes in the number, distribution and re-activity and cytokine responses of other members of the leukocytes-at least by FACS analysis of circulating immune cells-an easy to do experiment?

• Cancer is a very dynamic process which involves continuous evolution and natural selection. There exists high tumor variability- (cellular, genetic, epigenetic and immunological)-especially in advanced disease-such as a relapse after a few courses of radiotherapy and chemotherapy. How can an immune mediated killing overcome such heterogeneity (of epitopes evolved)?

Reference

1) Tran E et al. Science. 2014 May 9;344(6184):641-5.