PHA for aplastic anemias: the alpha but not the omega of mitogen therapies

This manuscript updates an analysis of the foremost clinical investigation of PHA for aplastic anemias and other disorders associated with impaired hematopoiesis during the years 1963-1967. Humble displayed remarkable insight in motivating the trials long before the recent era during which these disorders have become much better understood. That investigation actually consisted of a series of small pilot studies totaling only 44 patients involving all categories in the aplastic group and 15 miscellaneous disorders mostly neoplastic or premalignant. The most serious of several faults with the studies was the inadequacy of dosages applied, yet much better results were observed than might have been anticipated. Mitogens such as the L4 isolectin of PHA might be applied to treat aplastic anemias in three different ways. (1) For milder direct cytotoxicity types, a stimulating regimen should be applied to increase the production of growth factors and thereby hasten recovery from aplasia. (2) Where hematopoietic stem cell allo-engraftment is needed to replace severely damaged marrow, the mitogen should be included in the preparative regimen. (3) The suppressive protocol of a mitogen that maintains total T cell activation should be added to an established drug regimen such as cyclosporin and antilymphocyte globulin in treating the immuno-mediated aplastic anemias not only to provide superior suppression but to help prevent the late emergence of clonal disorders. The models of L4 isolectin application present advantages not fully offered by any of the other immuno-therapies currently available: broad scope of activities, low morbidity, ease of administration, favorable cost-effectiveness, assurance of reconstituted immune competence, and high potential for cure. However, a more potent mitogen than PHA-L4 not inhibited by serum glycoproteins or immunoglobulins and exhibiting a broader range of modulation would be preferred. A publication by Mann et al. in 1991 suggested that pokeweed mitogen (PWM) showing hundreds of times the potency of PHA-L4 would meet these criteria. Abbreviated reports on two of the studies in the report indicated that PWM had induced lasting remissions of cancers in dogs with nine injections in the mid-range of microgram doses over three weeks. The key study done by Mann himself demonstrated complete disappearance of canine gliomas in a carefully devised humane model applied to five dogs in which the transplantable tumor was established by extradural injection. Also impressive were lasting remissions of autonomous solid neoplasms in four dogs under the care of local veterinarians given PWM supplied by Mann. The critical aspect of these studies, both of which have been extended substantially, is the need keep the dosage within a precisely determined range to avoid loss of efficacy and possibly the occurrence of adverse effects. A review of basic studies now indicates the principle mechanism of response to be binding of PWM with tumor cells that then attract mast cells generated by stem cell factor the production of which is stimulated by the mitogen. Degranulation of mast cell granules releases TNF-alpha and IL-1 at the tumor site with resulting disappearance of neoplastic tissue in the absence of severe systemic effects. For cancer therapy, this represents a highly effective deviation from the stimulation of multiple pathways of immune response usually surmised with mitogens such as PHA-L4. This interpretation illustrates the probability that alternative plant mitogens, each with its unique properties, will likely become available to complement PHA-L4 or displace it from the prime standing as an immunomodulator.